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United States Patent |
5,700,810
|
Natsugari
,   et al.
|
December 23, 1997
|
Condensed heterocyclic compounds, their production and use
Abstract
Novel compound represented by the formula:
##STR1##
wherein A", B, C, D, E, G, Ar, X, Y, and Z are defined herein or a salt
thereof. The compounds have excellent activity of inhibiting ACAT,
lowering Cholesterol in blood and inhibiting tachykinin receptor, or a
salt thereof, their production and use.
Inventors:
|
Natsugari; Hideaki (Ashiya, JP);
Ikeda; Hitoshi (Higashiosaka, JP);
Ishimaru; Takenori (Toyonaka, JP);
Doi; Takayuki (Izumi, JP)
|
Assignee:
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Takeda Chemical Industries, Ltd. (Osaka, JP)
|
Appl. No.:
|
540913 |
Filed:
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October 11, 1995 |
Foreign Application Priority Data
| Sep 04, 1992[JP] | 4-237481 |
| Apr 28, 1993[JP] | 5-103328 |
Current U.S. Class: |
514/307; 514/309; 514/311; 514/312; 514/314; 546/141; 546/144; 546/157; 546/158; 546/165 |
Intern'l Class: |
C07D 215/14; C07D 217/04; A61K 031/47 |
Field of Search: |
546/141,144,157,158,165
514/309,307,312,314,311
|
References Cited
U.S. Patent Documents
3509156 | Apr., 1970 | Wei et al. | 546/157.
|
3798226 | Mar., 1974 | Meguro et al. | 546/159.
|
5198462 | Mar., 1993 | Natsugari | 514/432.
|
5264454 | Nov., 1993 | Meguro | 514/455.
|
5278186 | Jan., 1994 | Meguro | 514/457.
|
5527811 | Jun., 1996 | Natsugari | 514/309.
|
Foreign Patent Documents |
0 203 216 | Mar., 1986 | EP.
| |
0 354 994 | Feb., 1990 | EP.
| |
0 421 456 | Apr., 1991 | EP.
| |
0 481 383 | Apr., 1992 | EP.
| |
WO 91/09017 | Jun., 1991 | WO.
| |
WO 91/12249 | Aug., 1991 | WO.
| |
Other References
Vittorio, Farmaco, vol. 39(3), pp. 217-228, 1984.
Kohl, Journal of Pharmaceutical Sciences, vol. 62(12), pp. 2028-2030, 1973.
Shumakov, Khimiya Geterotsiklicheskikh Soedinenni, vol. 4, pp. 525-530,
1992.
Liu, Journal of the Taiwan Pharmaceutical Association, vol. 35(2), pp.
119-124, 1983.
Indian Journal of Chemistry, vol. 26B, Aug. 1987, pp. 744-747,
Pyrroloquinolines: Part I--Synthesis of 1-aryl-1 H-pyrrolo
›2,3-b!quinolines.
Japan Abstract for JP-221142-Sep. 2, 1987.
Egypt J. Chem. 28, No. 1, pp. 19-28 (1985) Reactions of
3-›N-(p-Tolylcarbamido)! -6-Bromocoumarin; Synthesis of
4-Dihydrocoumarins; 4-a-Chromene Acetic Acid, Benzopyranopyridones and
3,4,5,6-Tetrahydro-1,3-Benz. Deri.
Chemical Abstracts, vol. 114, 1991, p. 717, abstract No. 4249 q.
Egypt J. Chem. 28, No. 1, pp. 63-70 (1985) Action of Grignard Reagents and
of Ketones on 3-Phenyl Carbamoyl Coumarins.
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Mach; D. Margaret M.
Attorney, Agent or Firm: Foley & Lardner
Parent Case Text
This application is a division of application Ser. No. 08/114,841, filed
Sep. 2, 1993 now U.S. Pat. No. 5,482,967.
Claims
We claim:
1. A compound represented by the general formula:
##STR107##
wherein ring A" and ring B independently represent an optionally
substituted benzene ring;
either X or Y represents --NR.sup.1 -- (R.sup.1 represents a hydrogen atom,
an optionally substituted hydrocarbon group, an optionally substituted
hydroxyl group or an optionally substituted amino group), the other
representing --CO--, --CS-- or --C(R.sup.2)R.sup.2a -- (R.sup.2 and
R.sup.2a independently represent a hydrogen atom or an optionally
substituted hydrocarbon group), or either X or Y represents --N.dbd., the
other representing .dbd.CR.sup.3 -- (R.sup.3 represents a hydrogen atom, a
halogen atom, an optionally substituted hydrocarbon group, an optionally
substituted amino group, a substituted hydroxyl group or a mercapto group
substituted by an optionally substituted hydrocarbon group);
........ represent a single or double bond;
(i) when ........ adjacent to Z is a single bond, Z represents
##STR108##
(R.sup.4 represents a hydrogen atom, hydroxyl group or an optionally
substituted hydrocarbon group), or
(ii) when ........ adjacent to Z is a double bond, Z represents a carbon
atom;
D represents a C.sub.1-3 alkylene group which may be substituted by an oxo
group or a thioxo group, or D and Y, taken together, may form a 5- to 7-
membered ring which may be substituted by an oxo group or a thioxo group;
E represents --NR.sup.5 -- (R.sup.5 represents a hydrogen atom or an
optionally substituted hydrocarbon group), --O-- or --S(O)n-- (n is 0,1 or
2), or R.sup.5 and Y, taken together, may form a 5- to 7- membered ring
which may be substituted by an oxo group or a thioxo group;
G represents a bond or a C.sub.1-3 alkylene group;
Ar represents an optionally substituted aryl group, provided that (1) when
--X--Y-- represents --NH--CO--, D represents --CO--.
2. A compound as claimed in claim 1, wherein either X or Y represents
--NR.sup.1 --, the other representing --CO--, --CS-- or
--C(R.sup.2)R.sup.2a -- wherein R.sup.1, R.sup.2 and R.sup.2a represent
the same meanings as defined in claim 1.
3. A compound as claimed in claim 1, wherein --X--Y-- represents
--CO--NR.sup.1 -- or --NR.sup.1 --CO-- wherein R.sup.1 represents the same
meaning as defined in claim 1.
4. A compound as claimed in claim 1, wherein --X--Y-- represents --NR.sup.1
-- C(R.sup.2)R.sup.2a -- or --C(R.sup.2)R.sup.2a --NR.sup.1 -- wherein
R.sup.1, R.sup.2 and R.sup.2a represent the same meanings as defined in
claim 1.
5. A compound as claimed in claim 1, wherein --X--Y-- represents
--N.dbd.CR.sup.3 -- wherein R.sup.3 represents the same meaning as defined
in claim 1.
6. A compound as claimed in claim 1, wherein --X--Y-- represents
--CS--NR.sup.1 -- wherein R.sup.1 represents the same meaning as defined
in claim 1.
7. A composition for inhibiting acyl-CoA: cholesterol acyl transferase
which comprises an effective amount of a compound of the formula:
##STR109##
wherein ring A" and ring B independently represent an optionally
substituted benzene ring; either X or Y represents --NR.sup.1 -- (R.sup.1
represents a hydrogen atom, an optionally substitutedhydrocarbon group, an
optionally substituted hydroxyl group or an optionally substituted amino
group), the other representing --CO--, --CS-- or --C(R.sup.2)R.sup.2a --
(R.sup.2 and R.sup.2a respectively represent a hydrogen atom or an
optionally substituted hydrocarbon group), or either X or Y represents
--N.dbd., the other representing .dbd.CR.sup.3 -- (R.sup.3 represents a
hydrogen atom, a halogen atom, an optionally substituted hydrocarbon
group, an optionally substituted amino group, an optionally substituted
alkoxy group or a mercapto group substituted by an optionally substituted
hydrocarbon group);
........ represent a single or double bond;
(i) when ........ adjacent to Z is a single bond, Z represents
##STR110##
(R.sup.4 represents a hydrogen atom or an optionally substituted
hydrocarbon group), or (ii) when ........ adjacent to Z is a double bond,
Z represents a carbon atom;
D represents a C.sub.1-3 alkylene group which may be substituted by an oxo
group or a thioxo group, or D and Y, taken together, may form a 5- to 7-
membered ring which may be substituted by an oxo group or a thioxo group;
E represents --NR.sup.5 -- (R.sup.5 represents a hydrogen atom or an
optionally substituted hydrocarbon group), --O-- or --S(O)n-- (n is 0,1 or
2), or R.sup.5 and Y, taken together, may form a 5- to 7- membered ring
which may be substituted by an oxo group or a thioxo group;
G represents a bond or a C.sub.1-3 alkylene group;
Ar represents an optionally substituted aryl group or a pharmaceutically
acceptable salt and a physiologically acceptable carrier.
8. A composition for lowering cholesterol in blood which comprises an
effective amount of a compound as claimed in claim 7, or a
pharmaceutically acceptable salt and a physiologically acceptable carrier.
9. A tachykinin receptor antagonist composition which comprises an
effective amount of a compound as claimed in claim 7, or a
pharmaceutically acceptable salt and a physiologically acceptable carrier.
10. A substance P receptor antagonist composition which comprises an
effective amount of a compound as claimed in claim 7, or a
pharmaceutically acceptable salt and a physiologically acceptable carrier.
11. A process for producing a compound of claim 1 which comprises reacting
a compound of the formula:
##STR111##
wherein L represents a leaving group; D and Y do not bind together to form
a 5- to 7- membered ring; the other symbols are the same meaning as
defined in claim 1 or salt thereof with a compound of the formula:
H--E--G--Ar
wherein all symbols are the same meaning as defined in claim 1 or a salt
thereof.
12. A process for producing a compound of claim 1 which comprises reacting
a compound of the formula:
##STR112##
wherein all symboles are the same meaning as defined in claim 1 or salt
thereof with a compound of the formula:
L'G--Ar
wherein L' represents a leaving group; the other symbols are the same
meaning as defined in claim 1 or a salt thereof.
13. Method for treating hypercholesterolemia in mammals which comprises
administrating to a subject in need therefrom an effective amount of a
compound as claimed in claim 7 or a pharmaceutically acceptable salt and a
physiologically acceptable carrier.
14. Method for treating pain in mammals which comprises administrating to a
subject in need therefrom an effective amount of a compound as claimed in
claim 7 or a pharmaceutically acceptable salt and a physiologically
acceptable carrier.
15. Method for treating disturbances of micturition in mammals which
comprises administrating to a subject in need therefrom an effective
amount of a compound as claimed in claim 7 or a pharmaceutically
acceptable salt and a physiologically acceptable carrier.
16. Method for antagonizing a tachykinin recepter in mammals which
comprises administrating to a subject in need an effective amount of a
composition as claimed in claim 7 or a pharmaceutically acceptable salt
and a physiologically acceptable carrier.
17. A compound as claimed in claim 1, wherein ring A" represents a benzene
ring which may be substituted by two C.sub.1-4 alkyl groups; ring B
represents a benzene ring which may be substituted by a C.sub.1-4 alkyl
group or a halogen atom;
--X--Y-- represents --CO--NH--CH.sub.2 --or --CO--N(CH.sub.3)--;
Z represents a carbon atom;
........ represents a double bond;
--D--E--G-- represents --CONH--CH.sub.2 -- or --CON(CH.sub.3)--CH.sub.2 --;
and
Ar represents a phenyl group substituted by one or two optionally
halogenated C.sub.1-4 alkyl group(s).
18. A compound as claimed in claim 1, wherein ring A" and B represent an
unsubstituted benzene ring;
--X--Y-- represents --N.dbd.CH--, --N.dbd.CCl--, --N.dbd.C(NHCH.sub.3)--; Z
represents a carbon atom;
........ represents a double bond;
--D--E--G-- represents --CON(CH.sub.3)--CH.sub.2 --; and
Ar represents a phenyl group substituted by two optionally halogenated
C.sub.1-4 alkyl groups.
19. A compound as claimed in claim 1, wherein ring A" represents a benzene
ring which may be substituted by a halogen atom or a C.sub.1-4 alkyl
group;
ring B represents a benzene. ring which may be substituted by a halogen
atom;
--X--Y-- represents --N(CH.sub.3)--CO--, --N(CH.sub.3)--CH.sub.2 --,
--N.dbd.CH-- or --N.dbd.C(OCH.sub.3)--;
Z represents
##STR113##
........ represents a single bond or a double bond; --D--E--G-- represents
--CH.sub.2 --CONH--; and
Ar represents a phenyl group substituted by one to three optionally
halogenated C.sub.1-4 alkyl group(s), C.sub.1-4 alkoxy group(s) or halogen
atom(s).
20. A compound as claimed in claim 1 which is the general formula:
##STR114##
wherein rings A', B' and J independently represent an optionally
substituted benzene ring;
either X' or Y' represents --NR.sup.1a -- (R.sup.1a represents an
optionally substituted hydrocarbon group), the other representing --CO--,
--CS-- or --C(R.sup.2)R.sup.2a -- (R.sup.2 and R.sup.2a independently
represent a hydrogen atom or an optionally substituted hydrocarbon group),
or either X' or Y' represents --N.dbd., the other representing
.dbd.CR.sup.3a --(R.sup.3a represents a hydrogen atom, an optionally
substituted hydrocarbon group or --OR wherein R represents an optionally
substituted hydrocarbon group;
........ represents a single or double bond;
(i) when ........ is a single bond, Z' represents
##STR115##
(R.sup.4a represents a hydrogen atom or an optionally substituted
hydrocarbon group), or when ........ is a double bond, Z' represents a
carbon atom; .alpha. represents 0, 1 or 2, or a salt thereof.
21. A compound as claimed in claim 20, wherein --X'--Y'-- is the formula:
--NR.sup.1a --CO--, --NR.sup.1a --C(R.sup.2)R.sup.2a --, or
--N.dbd.CR.sup.3a --, wherein the symbols have the same definitions as in
claim 20.
22. A process for producing a compound represented by the general formula:
##STR116##
wherein the symbols have the same definitions as in claim 20, or a salt
thereof, characterized by reaction of a compound represented by the
general formula:
##STR117##
wherein the symbols have the same definitions as in claim 20, or a salt or
reactive derivative thereof, and a compound represented by the general
formula:
##STR118##
wherein the symbols have the same definitions as in claim 20, or a salt
thereof.
23. A composition for inhibiting acyl--CoA: cholesterol acyl transferace
which comprises an effective amount of a compound of the formula:
##STR119##
wherein rings A', B' and J independently represent an optionally
substituted benzene ring; either X" or Y" represents --NR.sup.1b --
(R.sup.1b represents a hydrogen atom or an optionally substituted
hydrocarbon group), the other representing --CO--, --CS-- or
--C(R.sup.2)R.sup.2a -- (R.sup.2 and R.sup.2a independently represent a
hydrogen atom or an optionally substituted hydrocarbon group), or either
X" or Y" represents --N.dbd., the other representing .dbd.CR.sup.3a --
(R.sup.3a represents a hydrogen atom, an optionally substituted
hydrocarbon group or --OR wherein R represents an optionally substituted
hydrocarbon group);
........ represents a single or double bond;
(i) when ........ adjacent to Z' is a single bond, Z' represents
##STR120##
(R.sup.4a represents a hydrogen atom or an optionally substituted
hydrocarbon group) or (ii) when ........ adjacent to Z' is a double bond,
Z'represents a carbon atom;
.alpha. represents 0, 1 or 2, or a pharmaceutically acceptable salt and a
physiologically acceptable carrier.
24. A compound as claimed in claim 1 which is the general formula:
##STR121##
wherein rings A" and B" are an optionally substituted benzene ring;
R.sup.1c represents a hydrogen atom, a hydroxyl group, an optionally
substituted hydrocarbon group, an optionally substituted alkoxy group or
an optionally substituted amino group;
Q represents an oxygen atom or a sulfur atom;
D.sup.1 represents a C.sub.1-3 alkylene group which may be substituted by
an oxo group or a thioxo group;
provided that when D.sup.1 is an unsubstituted C.sub.1-3 alkylene group, it
may cooperate with R.sup.1c to form a 5- to 7-membered ring which may be
substituted by an oxo or thioxo group;
E.sup.2 represents --NR.sup.5a -- (R.sup.5a represents a hydrogen atom or
an optionally substituted hydrocarbon group), --O-- or --S--;
R.sup.5a and R.sup.1c, take together, may form a 5- to 7-membered ring
which may be substituted by an oxo or thioxo group;
G.sup.3 represents a bond or a C.sub.1-3 alkylene group;
Ar' represents an optionally substituted aryl group provided that when
--D.sup.1 --E.sup.2 -- represents --(CH.sub.2).sub..beta.
--CONH--(.sub..beta. is 0, 1 or 2), G.sup.3 represents a C.sub.1-3
alkylene group, or a salt thereof.
25. A compound as claimed in claim 24, wherein rings A" and B" are a
benzene ring which may be substituted by one to four substituents selected
from the group consisting of a halogen, an optionally halogenated
C.sub.1-4 alkyl group, a hydroxyl group, an optionally halogenated
C.sub.1-4 alkoxy group, an optionally halogenated C.sub.1-4 alkylthio
group, an amino group, a mono- or di- C.sub.1-4 alkylamino group, a
carboxyl group and a C.sub.1-4 alkoxy-carbonyl group.
26. A compound as claimed in claim 24, wherein ring A" is represented by
the general formula:
##STR122##
wherein A.sup.4a, A.sup.5a and A.sup.6a, independently represent a halogen
atom, an optionally halogenated C.sub.1-4 alkyl group or an optionally
halogenated C.sub.1-4 alkoxy group.
27. A compound as claimed in claim 24, wherein ring B" is represented by
the general formula:
##STR123##
wherein B.sup.4b, B.sup.5b and B.sup.6b, independently represent a halogen
atom, an optionally halogenated C.sub.1-4 alkyl group or an optionally
halogenated C.sub.1-4 alkoxy group.
28. The compound as claimed in claim 24, wherein R.sup.1c is a hydrogen
atom or a C.sub.1-4 alkyl group which may be substituted by one or two
substituents selected from the group consisting of hydroxyl group,
C.sub.1-4 alkoxy group, amino group, mono- or di-C.sub.1-4 alkylamino
group, C.sub.1-4 alkoxy-carbonyl group, carboxyl group, carbamoyl group
and phenyl group.
29. A compound as claimed in claim 24, wherein R.sup.1c is a hydrogen atom
or a C.sub.1-4 alkyl group.
30. A compound as claimed in claim 24, wherein R.sup.5a is a hydrogen atom
or a C.sub.1-4 alkyl group which may be substituted by one or two
substituents selected from the group consisting of a hydroxyl group, a
C.sub.1-4 alkoxy group, an amino group, a mono- or di-C.sub.1-4 alkylamino
group, a C.sub.1-4 alkoxy-carbonyl group, carboxyl group, carbamoyl group
and phenyl group.
31. A compound as claimed in claim 24, wherein R.sup.5a is a hydrogen atom
or a C.sub.1-4 alkyl group.
32. A compound as claimed in claim 24, wherein the optionally substituted
aryl group represented by Ar, is a C.sub.6-10 aryl group which may be
substituted by one to three substituents selected from the group
consisting of an optionally halogenated C.sub.1-4 alkyl group, a halogen
atom, a nitro group, a hydroxyl group, an optionally halogenated C.sub.1-4
alkoxy group, an amino group, a mono- or di-C.sub.1-4 alkylamino group, a
C.sub.1-4 alkoxy-carbonyl group, a Carboxyl group and a carbamoyl group.
33. A compound as claimed in claim 24, wherein Ar is a phenyl group which
may have one to three substituents selected from the group consisting of
an optionally halogenated C.sub.1-4 alkyl group, halogen atom and
C.sub.1-4 alkoxy group.
34. A compound as claimed in claim 24, wherein Q is an oxygen atom.
35. A compound as claimed in claim 24, wherein D.sup.1 is --CO--, --CS--,
--CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CO-- or --CH.sub.2
CH.sub.2 CO--.
36. A compound as claimed in claim 24 wherein D.sup.1 is --CO-- or
--CH.sub.2 CO--.
37. A compound as claimed in claim 24, wherein D.sup.1 is --CH.sub.2 -- or
--CH.sub.2 CH.sub.2 --.
38. A compound as claimed in claim 24, wherein D.sup.1 is --CO-- or
--CH.sub.2 --.
39. A compound as claimed in claim 24, wherein E.sup.2 is --NR.sup.5c --
wherein R.sup.5c is a hydrogen atom or a C.sub.1-4 alkyl group.
40. A compound as claimed in claim 24, wherein E.sup.2 is --O--.
41. A compound as claimed in claim 24, wherein G.sup.3 is --CH.sub.2 -- or
--CH.sub.2 CH.sub.2 --.
42. A compound as claimed in claim 24; wherein ring A" is a benzene ring
which may be substituted by two C.sub.1-4 alkyl groups;
ring B" is a benzene ring which may be substituted by a C.sub.1-4 alkyl
group;
R.sup.1c is a C.sub.1-4 alkyl group;
D.sup.1 is --CO--;
E.sup.2 is --NR.sup.5c -- wherein R.sup.5c represents a hydrogen atom or a
C.sub.1-4 alkyl group;
G.sup.3 is --CH.sup.2 --; and
Ar is a phenyl group substituted by one to three halogenated C.sub.1-4
alkyl groups.
43. A compound as claimed in claim 24 which is
N-(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1
-oxo-3-isoquinolinecarboxsmide,
N-(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-N,2-dimethyl-4-(2-methylpheny
l)-1-oxo-3-isoquinolinecarboxamide or
bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl
-3-isoquinolinecarboxamide.
44. A tachykinin receptor antagonist composition containing a compound
represented by the general formula:
##STR124##
wherein rings A" and B" are an optionally substituted benzene ring;
R.sup.1c represents a hydrogen atom, a hydroxyl group, an optionally
substituted hydrocarbon group, an optionally substituted alkoxy group or
an optionally substituted amino group;
Q represents an oxygen atom or a sulfur atom;
D.sup.1 represents a C.sub.1-3 alkylene group which may be substituted by
an oxo or thioxo group;
provided that when D.sup.1 is an unsubstituted C.sub.1-3 alkylene group, it
may cooperate with R.sup.1c to form a 5- to 7-membered ring which may be
substituted for by an oxo or thioxo group;
E.sup.2 represents --NR.sup.5a -- (R.sup.5a represents a hydrogen atom or
an optionally substituted hydrocarbon group), --O-- or --S--;
R.sup.5a and R.sup.1c may bind together to form a 5- to 7-membered ring
which may be substituted by an oxo or thioxo group;
G.sup.3 represents a bond or a C.sub.1-3 alkylene group;
Ar' represents an optionally substituted aryl group;
provided that when D.sup.1 is --(CH.sub.2).sub..beta. --CO-- (.sub..beta.
is 0, 1 or 2) and D.sup.2 is --NH--, Z represents a C.sub.1-3 alkylene
group, or a pharmaceutically acceptable salt and a pharmaceutically
acceptable carrier.
45. A tachykinin receptor antagonist composition containing the compound of
claim 24.
46. a tachykinin antagonist of claim 44 wherein the tachykinin receptor is
a substance P receptor.
47. A substance P receptor antagonist composition containing the compound
of claim 24.
48. A process for producing a compound of claim 24 which comprises reacting
a compound of the formula:
##STR125##
wherein L represents a leaving group; D.sup.1 and R.sup.1c do not bind
together to form a 5- to 7- membered ring; the other symboles are the same
meaning as defined in claim 24 or a salt thereof with a compound of the
formula:
H--E--G--Ar
wherein all symboles are the sine meanings as defined in claim 24 or a salt
thereof.
49. A process for producing a compound of claim 24 which comprises reacting
a compound of the formula:
##STR126##
wherein all symboles are the same meaning as defined in claim 24 or salt
thereof with a compound of the formula:
L'--G--Ar
wherein L' represents a leaving group; the other symboles are the same
meaning as defined in claim 24 or a salt thereof.
50. A compound as claimed in claim 1, which is;
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-ethyl-2-methyl-1-oxo-4-phe
nyl-3-isoiquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-5-fluoro-4-(4-fluorophenyl)-N,2-dimethyl
-1-oxo-3-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-ethyl-N-methyl-1-oxo-4-phe
nyl-3-isoiquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2-methylphenyl)-
1-oxo-3-isoiquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-2-oxo-4-phenyl-3-qu
inolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-N,1-dimet
hyl-2-oxo-3-quinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1-chloro-4-(4-fluorophenyl)-N-methyl-3-i
soquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-4-(2-methylphen
yl)-1-oxo-3-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-
3-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N,2-dimet
hyl-1-oxo-3-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3
-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluoro-2-methylphenyl)-1,2-dihydro-
N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N-methyl-
1-oxo-3-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2,5,6,7,8-hexahydro-N,2-dimethyl-1-oxo
-4-phenyl-3-isoquinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,1-dimethyl-2-oxo-4-phenyl-
3-quinolinecarboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-phenyl-3-quinolinecarboxamide
N-›3,5-Bis(trifluoromethyl)benzyl!-N,2-dimethyl-4-phenyl-3-quinolinecarboxa
mide,
N-›3,5-Bis(trifluoromethyl)benzyl!-2-chloro-N-methyl-4-phenyl-3-quinolineca
rboxamide,
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-methylamino-4-phenyl-3-quinol
inecarboxamide or
N-›3,5-Bis(trifluoromethyl)benzyl!-1-chloro-N-methyl-4-phenyl-3-isoquinolin
ecarboxarnide, or a salt thereof.
51. A method of preparing a tachykinin receptor antagonizing composition,
comprising combining a therapeutically effective amount of the compound of
claim 1 or a pharmaceutically acceptable salt with a physiologically
acceptable carrier.
52. A method of preparing an inhibitory composition for the biosynthesis of
cholesterol, comprising combining a therapeutically effective amount of
the compound of claim 1 or a pharmaceutically acceptable salt with a
physiologically acceptable carrier.
Description
The present invention relates to a new condensed heterocyclic compound
which excellently inhibits the enzyme acyl-CoA:cholesterol acyl
transferase (ACAT) and has a high tachykinin receptor antagonizing
activity.
With respect to the compound wherein a phenyl group and a group of the
formula:
##STR2##
(m is 0 or 1) adjacently substitute on a heterocyclic ring resulting from
condensation of a 6-membered heterocyclic ring and a benzene ring, known
compounds include (1) the compound represented by the formula:
##STR3##
wherein Ar represents an aryl group, described in the Indian Journal of
Chemistry, Section B, 26B, Vol. 8, pp. 744-747 (1987), (2) the compound
represented by the formula:
##STR4##
wherein R.sup.1 represents an alkyl, aryl or cyclohexyl group, described
in the Chemical Abstract, Vol. 107, 175835f, (3) the compound represented
by the formula:
##STR5##
wherein R represents benzyl or 4-methylphenyl and R.sup.1 represents a
methyl, ethyl, naphthyl, benzyl or phenyl group, described in the Chemical
Abstract, Vol. 114, 42492q, (4) the compound represented by the formula:
##STR6##
wherein Ph represents a phenyl group; R.sup.1 represents an hydrogen atom
or bromine; R.sup.2 represents an alkyl, aryl or benzyl group, described
in the Chemical Abstract, Vol. 107, 115463y, and (5) the compound
represented by the formula:
##STR7##
wherein R.sup.2 represents a phenyl, o-, m- or p-methylphenyl or
4-chlorophenyl group; R.sup.3 represents a phenyl, benzyl, allyl, ethyl,
butyl, isobutyl or t-butyl group, described in the Chemical Abstract, Vol.
93, 220536q.
Also, publication (1) describes that pyrrolo›2,3-b!quinoline series
compounds exhibit anti-inflammatory, antibacterial, hypotensive,
antipyretic and antispasmodic actions and possess interferon-inducing
activity. As for publications (2) to (5), no action is described but
methods of synthesizing the respective compounds are described.
However, there have been no reports concerning whether these conventional
compounds exhibit ACAT-inhibitory action, arteriosclerosis therapeutic
effect, blood cholesterol lowering action and tachykinin receptor
antagonizing action.
As compounds having substance P receptor antagonizing activity, the
following (6) to (13) are known. (6) In EP-A-333,174, a compound of the
formula:
R.sup.1 --A--D-Trp(R.sup.2)-Phe-R.sup.3
wherein R.sup.1 is hydrogen or an amino-protecting group; R.sup.2 is
hydrogen, an amino-protecting group, a carbamoyl(lower)alkyl group, a
carboxy(lower)alkyl group; R.sup.3 is an ar(lower)alkyl group, a group of
the formula:
##STR8##
wherein R.sup.4 and R.sup.5 are each hydrogen, aryl or lower alkyl which
may have suitable substituent(s), or R.sup.4 and R.sup.5 are linked
together to form benzene-condensed lower alkylene or a group of the
formula:
--OR.sup.6
wherein R.sup.6 is hydrogen, aryl or lower alkyl which may have suitable
substituent(s); A is a single bond or one or two amino acids residue,
provided when A is one amino acid residue of --D-Trp--, then R.sup.4 is
not hydrogen; and a salt thereof, (7) in EP-A-436,334 among others, a
compound of the formula:
##STR9##
(8) in EP-A-429,366 among others, a compound of the formula:
##STR10##
(9) in Journal of Medicinal Chemistry, 34, p1751, 1991 among others, a
compound of the formula:
##STR11##
(10) in WO91/09844, a compound of the formula:
##STR12##
(11) in EP-A-522,808, a compound of the formula:
##STR13##
(12) in WO93/01169, a compound of the formula:
##STR14##
(13) in EP-A-532,456, a compound of the formula:
##STR15##
And, the following (14), (15) and (16) are known for isoquinoline
derivatives. (14) in Farmaco, Edizione Scientifica, 36, 400-411 (1981), a
compound of the formula:
##STR16##
(15) in Chemical Abstract, 107, 39507(1987), a compound of the formula:
##STR17##
(16) Archiv der Pharmazie, 324, 809-814 (1991), a compound of the formula:
##STR18##
wherein R.sup.1 represents hydrogen, methyl, n-butyl, cyclohexyl, benzyl,
isopropyl; R.sup.2 represents hydrogen, 10-methyl, 11-methyl, 10-chloro,
11-chloro, 12-fluoro, 12-bromo; R.sup.3 represents hydrogen, 6-chloro,
7-chloro, 6-bromo.
With respect to a bioactivity of a compounds described in (14) to (16),
there is disclosure about local anesthesia action in (14), antibacterial
action in (15) and anticonvulsion action in (16). However, there is no
disclosure ever suggesting that these compounds have ACAT-inhibitory
action, blood cholesterol lowering action and tachykinin receptor
antagonizing action.
Against this background, there has been demand for the development of a
compound which exhibits excellent ACAT-inhibitory action, which suppresses
intestinal cholesterol absorption and arterial wall cholesterol ester
accumulation in mammals, and which is useful as a prophylactic and
therapeutic composition for hypercholesterolemia, atheromatous
arteriosclerosis and various diseases associated therewith (e.g., ischemic
heart diseases such as myocardial infarction and cerebrovascular disorders
such as cerebral infarction and cerebral stroke).
And, tachykinin is a generic term denoting a group of neuropeptides. In
mammalian animals, substance P, neurokinin-A and neurokinin-B are known.
It is also known that by binding their respective receptors (neurokinin-1,
neurokinin-2, neurokinin-3) present in the living body, these peptides
exhibit a diversity of biological activities.
Among them, substance P is a neuropeptide known for the longest time of all
and studied in the greatest detail. Substance P is known to play a
critical role as a transmitter substance in both the peripheral and
central nervous systems. This substance is also suspected to be involved
in a variety of morbid states (pain, inflammation, allergy, faciltation of
micturition, mental disease, airway-diseases, etc.). Such being the case,
for use as drugs for the treatment of the above-mentioned disease states,
the development of compounds having potent tachykinin receptor
antagonizing activity, particularly high antagonistic activity against
substance P receptor, as well as other favorable properties such as safety
and a sufficiently long duration of action after administration has been
looked after in earnest.
This invention concerns certain heterocyclic compounds which inhibit the
enzyme ACAT, pharmaceutical compositions containing these compounds, and a
method of treating hypercholesterolemia and artherosclerosis and so on,
and antagonize the tachykinin receptor, pharmaceutical compositions
containing these compounds, and a method of treating pain, disturbances of
micturition and inflammation and so on.
(1) A compound of this invention is represented by the following general
formula:
##STR19##
wherein ring A may be substituted; ring B represents an optionally
substituted benzene ring;
either X or Y represents --NR.sup.1 -- (R.sup.1 represents a hydrogen atom,
an optionally substituted hydrocarbon group, an optionally substituted
hydroxyl group or an optionally substituted amino group), --O-- or --S--,
the other representing --CO--, --CS-- or --C(R.sup.2)R.sup.2a -- (R.sup.2
and R.sup.2a independently represent a hydrogen atom or an optionally
substituted hydrocarbon group), or either X or Y represents --N.dbd., the
other representing .dbd.CR.sup.3 -- (R.sup.3 represents a hydrogen atom, a
halogen atom, an optionally substituted hydrocarbon group, an optionally
substituted amino group, a substituted hydroxyl group or a mercapto group
substituted by an optionally substituted hydrocarbon group);
........ represents a single or double bond;
(i) when ........ adjacent to Z is a single bond, Z represents
##STR20##
(R.sup.4 represents a hydrogen atom, a hydroxyl group or an optionally
substituted hydrocarbon group) or a nitrogen atom, or (ii) when ........
adjacent to Z is a double bond, Z represents a carbon atom;
D represents a C.sub.1-3 alkylene group which may be substituted by an oxo
or thioxo group, or D and Y, taken together, may form a 5- to 7- membered
ring which may be substituted by an oxo or thioxo group;
E represents --NR.sup.5 -- (R.sup.5 represents a hydrogen atom or an
optionally substituted hydrocarbon group), --O-- or --S(O)n-- (n is 0,1 or
2), or R.sup.5 and Y, taken together, may form a 5- to 7-membered ring
which may be substituted by an oxo or thioxo group;
G represents a bond or a C.sub.1-3 alkylene group;
Ar represents an optionally substituted aryl group or an optionally
substituted heterocyclic group, provided that, (1) when (i)
--X--Y--represents --O--CO-- or --CO--O--, (ii) D represents --CO-- and
(iii) E represents --NR.sup.5 --, either (a) G represents a C.sub.1-3
alkylene group and Ar represents a substituted aryl group or a substituted
heterocyclic group, or (b) G represents a bond and R.sup.5 represents an
optionally substituted hydrocarbon group, and (2) when --X--Y-- represents
--NH--CO--, D represents --CO--, or a salt thereof, (2) a composition for
inhibiting acyl-CoA: cholesterol acyl transferase, lowering cholesterol in
blood and having tachykinin receptor antagonizing activity which comprise
an effective amount of a compound of the formula:
##STR21##
wherein the symbols are as defined above excluding for the "provided"
clause, or a pharmaceutically acceptable salt and a physiologically
acceptable carrier, (3) a process for producing the above compound (I) or
a salt thereof which comprises reacting a compound of the formula:
##STR22##
wherein L represents a leaving group; D and Y do not bind together to form
a 5- to 7-membered ring; the other symbols are the same meaning as defined
hereinabove or salt thereof with a compound of the formula:
H--E--G--Ar (III)
wherein all symboles are the some meaning as defined hereinabove or a salt
thereof, (4) a process for producing the above compound (I) or a salt
thereof, which comprises reacting a compound of the formula:
##STR23##
wherein all symboles are the same meaning as defined hereinabove or salt
thereof with a compound of the formula:
L'--G--Ar (V)
wherein L' represents a leaving group; the other symboles are the same
meaning as defined hereinabove or a salt thereof.
With respect to the above formula, the ring A represents an optionally
substituted ring. The ring A represents a moiety of the formula:
##STR24##
The ring B represents an optionally substituted benzene ring. Preferably,
the ring A and B each is a benzene ring which may be substituted.
The substituent(s) that may be present on ring A and B include, among
others, halogen atom, optionally halogenated alkyl group, optionally
halogenated alkoxy group, optionally halogenated alkylthio group,
C.sub.1-7 acylamino group (e.g. formylamino, acetylamino, propionylamino,
butyrylamino, benzoylamino, etc.), C.sub.1-3 acyloxy group (e.g.
formyloxy, acetoxy, propionyloxy, etc.), hydroxyl, nitro, cyano, amino,
mono- or di-C.sub.1-4 alkylamino group (e.g. methylamino, ethylamino,
propylamino, dimethylamino, diethylamino, etc.), cyclic amino group (e.g.,
5- to 9-membered cyclic amino which may consist 1 to 3 hetero-atoms such
as oxygen and sulfur in addition to nitrogen as ring-constituent members,
such as pyrrolidino, piperidino, morpholino, etc.), C.sub.1-4
alkyl-carbonylamino group (e.g. acetylamino, propionylamino, butyrylamino,
etc.), C.sub.1-4 alkylsulfonylamino group (e.g. methylsulfonylamino,
ethylsulfonylamino, etc.), C.sub.1-4 alkoxy-carbonyl group (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl,
C.sub.1-6 alkyl-carbonyl group (e.g. methylcarbonyl, ethylcarbonyl,
propylcarbonyl, etc.), carbamoyl, ethylcarbamoyl, etc.), mono- or
di-C.sub.1-4 alkylcarbamoyl group(e.g. methylcarbamoyl, ethylcarbamoyl,
etc.:) and C.sub.1-6 alkylsulfonyl group (e.g. methylsulfonyl,
ethylsulfonyl, propylsulfonyl, etc.).
As the halogen atom, among the above-mentioned substituents, fluoro,
chloro, bromo and iodo may be used and chloro or fluoro is preferred.
Examples of the optionally halogenated alkyl group include straight-chain
or branched alkyl group having 1 to 6 carbon atoms and such alkyl groups
substituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine and
iodine, preferably chlorine, bromine etc.). Specifically, commonly used
alkyl group include methyl, chloromethyl, difluoromethyl, trichloromethyl,
trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,
pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl,
2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl,
4-trifluoromethyl-butyl, hexyl, 6,6,6-trifluorohexyl and
5-trifluoromethylpentyl. Preferably used are straight-chain or branched
alkyl groups having 1 to 4 carbon atoms such as methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl,
2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl
and tert-butyl, or such alkyl groups substituted for by 1 to 3 of the
above-mentioned halogen atoms.
Examples of the alkoxy group which may be substituted by halogen and the
alkylthio group which may be substituted by halogen include alkoxy group
which may be substituted by halogen and alkylthio groups which may be
substituted for by halogen, resulting from binding of either the
above-exemplified alkyl group or such alkyl group substituted for halogen
and either an oxygen atom or a sulfur atom, respectively.
Examples of the optionally substituted alkoxy group include straight-chain
or branched alkoxy group having 1 to 6 carbon atoms or such alkoxy group
substituted by 1 to 5 of the above-mentioned halogen atoms. Specifically,
commonly used alkoxy group include methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,
butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy and
hexyloxy. Preferably used are straight-chain or branched alkoxy groups
having 1 to 4 carbon atoms such as methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,
butoxy, 4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy, or such alkoxy
group substituted for by 1 to 3 of the above-mentioned halogen atoms.
Examples of the optionally substituted alkylthio group include
straight-chain or branched alkylthio group having 1 to 6 carbon atoms or
such alkylthio group substituted for by 1 to 5 of the above-mentioned
halogen atoms. Specifically, commonly used alkylthio groups include
methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio
and hexylthio. Preferably used are straight-chain or branched alkylthio
groups having 1 to 4 carbon atoms such as methylthio, difluoromethylthio,
trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio and
4,4,4-trifluorobutylthio, or such alkylthio groups substituted for by 1 to
3 of the above-mentioned halogen atoms.
Preferable substituents on ring A and B include halogen (e.g. fluoro,
chloro, bromo, etc.), optionally halogenated C.sub.1-4 alkyl (e.g. methyl,
chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluropropyl,
isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl, tert-butyl, etc.), optionally halogenated C.sub.1-4 alkoxy
(e.g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy,
isobutoxy, sec-butoxy, etc.), optionally substituted C.sub.1-4 alkylthio
(e.g. methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
propylthio, isopropylthio, buthylthio, 4,4,4-trifluorobuthylthio, etc.),
C.sub.1-3 acyloxy (e.g. formyloxy, acetoxy, propionyloxy, etc.), hydroxyl,
amino, mono-or di-C.sub.1-4 alkylamino (e.g. methylamino, ethylamino,
propylamino, dimethylamino, diethylamino, etc.), carboxyl and C.sub.1-4
alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
etc.).
More preferable substituents on ring A and B include halogen (e.g. fluoro,
chloro, bromo, etc.), optionally halogenated C.sub.1-4 alkyl (e.g. methyl,
chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl,
isopropyl, 2-trifluoromethylethyl, buthyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl, tert-butyl, etc.), optionally halogenated C.sub.1-4 alkoxy
(e.g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy,
isobutoxy, sec-butoxy, etc.), hydroxyl, amino, mono- or di- C.sub.1-4
alkylamino (e.g. methylamino, ethylamino, propylamino, dimethylamino,
diethylamino, etc.) and C.sub.1-3 acyloxy (e.g. formyloxy, acetoxy,
propionyloxy, etc.).
Specifically more preferable substituents on ring A and B include halogen
(e.g. fluoro, chloro, bromo, etc.), optionally halogenated C.sub.1-4 alkyl
(e.g. methyl, chloromethyl, difluoromethyl, trichloromethyl,
trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, buthyl,
4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, etc.), optionally
halogenated C.sub.1-4 alkoxy (e.g. methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,
butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.).
The substituent(s) for rings A and B may be located at any position on the
ring. When two or more substituents are present, they may be identical or
not, the number of substituents being 1 to 4, preferably 1 to 3, more
preferably 1 or 2. Also, the adjacent carbons on ring A or B may bind with
a group represented by --(CH.sub.2)l-- (l represents an integer of from 3
to 5) to form a 5- to 7-membered ring.
I). Some Examples of Ring A and B
Ring A is preferably a benzene ring which may be substituted by one to four
substituents selected from the group consisting of halogen (e.g.,
fluorine, chlorine, bromine, etc.), optionally halogenated C.sub.1-4 alkyl
group (e.g., methyl, ethyl, isopropyl, trifluoromethyl etc.) and
optionally halogenated C.sub.1-4 alkoxy group (e.g., methoxy
trifluoromethoxy, ethoxy, etc.), specifically a benzene ring which may be
substituted and which is represented by formula ›A!:
##STR25##
wherein A.sup.1, A.sup.2 and A.sup.3, whether identical or not,
independently represent a hydrogen, a halogen (e.g., fluorine, chlorine,
etc.), an optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl, ethyl, isopropyl, etc.) or an optionally halogenated
C.sub.1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, ethoxy, etc.).
More preferably, for example, there may be used benzene ring which may be
substituted and which is represented by the above formula ›A! wherein:
(1) A.sup.1, A.sup.2, and A.sup.3 are all hydrogen,
(2) A.sup.1 and A.sup.2 are both hydrogen, A.sup.3 being a halogen (e.g.
fluorine, chlorine, etc.), an optionally halogenated C.sub.1-4 alkyl
group(e.g. methyl, trifluoromethyl, ethyl, etc.) or an optionally
halogenated C.sub.1-4 alkoxy group (e.g. methoxy, trifluoromethoxy,
ethoxy, etc.),
(3) A.sup.1 is hydrogen, A.sup.2 and A.sup.3, whether identical or not,
being independently a halogen (e.g. fluorine, chlorine), a C.sub.1-4 alkyl
group (e.g. methyl, ethyl, etc.) or a C.sub.1-4 alkoxy group (e.g.
methoxy, ethoxy, etc.), or
(4) A.sup.2 is hydrogen, A.sup.1 and A.sup.3, whether identical or not,
being independently a C.sub.1-4 alkyl group (e.g. methyl, ethyl, etc.).
More preferably for ring A, for example, there may be used benzene rings
which may be substituted and which is represented by the above formula ›A!
wherein:
(a) A.sup.1, A.sup.2 and A.sup.3 are all hydrogen,
(b) A.sup.1 and A.sup.2 are both hydrogen, A.sup.3 being chlorine, a
methyl, ethyl, isopropyl, methoxy or trifluoromethyl group,
(c) A.sup.1 is hydrogen, A.sup.2 and A.sup.3 being both a methyl or methoxy
group, or
(d) A.sup.2 is hydrogen, A.sup.1 and A.sup.3 being both a methyl group.
Ring B is preferably a benzene ring which may be substituted by one to four
substituents selected from the group consisting of a halogen (e.g.,
fluorine, chlorine, etc.), an optionally halogenated C.sub.1-4 alkyl group
(e.g., methyl, trifluoromthyl, ethyl etc.) and, an optionally halogenated
C.sub.1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, ethoxy etc.),
specifically a benzene ring which may be substituted and which is
represented by formula ›B!:
##STR26##
wherein B.sup.1, B.sup.2 and B.sup.3, whether identical or not,
independently represent hydrogen, a halogen (e.g., fluorine, chlorine,
etc.), an optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethoxy, ethyl, etc.) or an optionally halogenated C.sub.1-4
alkoxy group (e.g., methoxy, trifluoromethoxy ethoxy, etc.). More
preferably, for example, there may be used benzene ring which may be
substituted and which is represented by the above formula ›B! wherein:
(1) B.sup.1, B.sup.2 and B.sup.3 are all hydrogen,
(2) B.sup.1 is halogen (e.g. fluorine, chlorine, etc.), an optionally
halogenated C.sub.1-4 alkyl group (e.g. methyl, trifluoromethyl, ethyl,
etc.) or an optionally halogenated C.sub.1-4 alkoxy group (e.g. methoxy,
trifluoromethoxy, ethoxy, etc.), B.sup.2 and B.sup.3 being both hydrogen,
(3) B.sup.1 is hydrogen, B.sup.2 and B.sup.3, whether identical or not,
being independently an optionally halogenated C.sub.1-4 alkoxy group (e.g.
methoxy, trifluoromethoxy, ethoxy, etc.), or
(4) B.sup.1, B.sup.2 and B.sup.3, whether identical or not, are
independently a C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy, etc.).
More preferably for ring B, for example, there may be used benzene rings
which may be substituted for and which is represented by the above formula
›B! wherein:
(a) B.sup.1, B.sup.2 and B.sup.3 are all hydrogen,
(b) B.sup.1 is chlorine, fluorine, a methyl, trifluoromethyl or methoxy
group, B.sup.2 and B.sup.3 being both hydrogen,
(c) B.sup.1 is hydrogen, B.sup.2 and B.sup.3 being both a methoxy group, or
(d) B.sup.1, B.sup.2 and B.sup.3 are all a methoxy group.
II). Other Examples of Ring A and B
Referring to ring A, concrete examples of the moiety
##STR27##
include groups of the formula:
##STR28##
where A.sup.4, A.sup.5 and A.sup.6 are the same or different and each
means a halogen atom such as fluoro, chloro, etc., an optionally
halogenated C.sub.1-4 alkyl group such as methyl, ethyl, isopropyl
trifluoromethyl, etc., or an optionally halogenated C.sub.1-4 alkoxy group
such as methoxy, trifluoromethoxy, ethoxy, etc.
Preferred examples of ring A are groups of the formula:
##STR29##
wherein A.sup.7 and A.sup.8 represents a halogen atom (e.g. fluorine,
chlorine, etc.), an optionally halogenated C.sub.1-4 alkyl group (e.g.,
methyl, trifluoromethyl, ethyl, etc.). More preferably, for example, there
may be used benzene ring which may be substituted and which is represented
by the above formula wherein
(1) A.sup.4 is a halogen (e.g. fluorine, chlorine, etc.) or an optionally
halogenated C.sub.1-4 alkyl group (e.g., methyl, trifluoromethyl, ethyl,
propyl)
(2) A.sup.5 and A.sup.6 are an optionally halogenated a C.sub.1-4 alkyl
group (e.g., methyl, trifluoromethyl, ethyl, etc.) or a C.sub.1-4 alkoxy
group (e.g., methoxy, ethoxy, etc.),
(3) A.sup.7 and A.sup.8 are a C.sub.1-4 alkyl group (e.g. methyl, ethyl,
etc.),
(4) A.sup.4 is a halogen (e.g., fluorine, chlorine, etc.),
(5) A.sup.5 and A.sup.6 are a C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy,
etc.),
Referring to ring B, concrete examples of the moiety
##STR30##
include groups of the formula:
##STR31##
where in B.sup.4, B.sup.5, B.sup.6, B.sup.7, B.sup.8 and B.sup.9 are the
same or different and each means a halogen atom such as chloro, fluoro,
etc., an optionally halogenated C.sub.1-4 alkyl group such as methyl,
trifluoromethyl, ethyl, etc., or an optionally halogenated C.sub.1-4
alkoxy group such as methoxy trifluoromethoxy, ethoxy, etc.
Preferred examples of the ring B are groups of the formula:
##STR32##
wherein B.sup.4, B.sup.5 and B.sup.6 is the same meaning hereinbefore.
Particularly preferred examples are groups of the formula:
##STR33##
wherein B.sup.10 is an optionally halogenated C.sub.1-4 alkyl group (e.g.,
methyl, trifluoromethyl, ethyl, etc.).
More preferably, for example, there may be used benzene rings which may be
substituted and which is represented by the above formula wherein:
(1) B.sup.4 is a halogen (e.g., fluoro, chrolo etc.) or an optionally
halogenated C.sub.1-4 alkyl group (e.g., methyl, trifluoromethyl, ethyl,
etc.)
(2) B.sup.5 and B.sup.6, whether identical or not, being independently an
optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl, ethyl, etc.).
(3) B.sup.4 is an optionally halogenated C.sub.1-4 alkoxy group (e.g.,
methoxy, trifluoromethoxy, ethoxy, etc.)
(4) B.sup.5 and B.sup.6, whether identical or not, being independently an
optionally halogenated C.sub.1-4 alkoxy group (e.g., methoxy,
trifluoromethoxy, ethoxy, etc.)
With respect to the above formulas, R.sup.1 represents a hydrogen atom, an
optionally substituted hydrocarbon group, an optionally substituted
hydroxyl group or an optionally substituted amino group.
R.sup.2 and R.sup.2a independently represent a hydrogen atom or an
optionally substituted hydrocarbon group.
R.sup.3 represents a hydrogen atom, a halogen atom, an optionally
substituted hydrocarbon group, an optionally substituted amino group, a
substituted hydroxyl group or a mercapto group substituted by an
optionally substituted hydrocarbon group.
R.sup.4 represents a hydrogen atom, a hydroxyl group or an optionally
substituted hydrocarbon group.
R.sup.5 represents a hydrogen atom or an optionally substituted hydrocarbon
group.
The hydrocarbon group described hereinabove include alkyl group, alkenyl
group, alkynyl group, cycloalkyl group and aryl group. etc.
Preferable examples of hydrocarbon group are an alkyl group, a cycloalkyl
group and an aryl group, and more preferable examples are an alkyl group.
The alkyl group includes a straight-chain or branched alkyl group having 1
to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., preferably a
straight-chain or branched alkyl group having 1 to 4 carbon atoms such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or
tert-butyl, etc.
The alkenyl group includes alkenyl group having 2 to 6 carbon atoms such as
ethenyl, propenyl, isopropenyl, butenyl, isobutenyl or sec-butenyl, etc.,
preferably an alkenyl group having 2 to 4 carbon atoms such as ethenyl,
propenyl or isopropenyl, etc.
The alkynyl group includes alkynyl group having 2 to 6 carbon atoms such as
ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, etc., or sec-butynyl,
etc., preferably an alkynyl group having 2 to 4 carbon atoms such as
ethynyl, propynyl or isopropynyl, etc.
The cycloalkyl group includes a C.sub.3-8 cycloalkyl group such as
cyclopropyl, cyclobutyl, cyclopentyl, etc., or cyclohexyl, preferably a
C.sub.3-6 cycloalkyl group such as cyclopropyl or cyclobutyl, etc.
The aryl group includes aryl group having 6 to 14 carbon atoms such as
phenyl, naphthyl, anthryl or phenanthryl etc., preferably an aryl group
having 6 to 10 carbon atoms such as phenyl or naphthyl, and more
preferably a phenyl group.
Examples of the substituent for the optionally substituted hydrocarbon
group include (i) halogen, (ii) cycloalkyl group, (iii) aryl group, (iv)
amino group which may have an alkyl, alkenyl, cycloalkyl or aryl group as
a substituent, (v) hydroxyl group, (vi) optionally halogenated alkoxy
group (vii) acyl group, (viii) acyloxy group, (ix) cyano group, (x)
optionally protected carboxyl group (xi) carbamoyl groups, (xii) mercapto
group, (xiii) alkylthio group, (xiv) sulfo group and (xv) alkylsulfonyl
group.
The optionally substituted hydrocarbon group may be substituted for by 1 to
4, preferably 1 or 2 of the above-mentioned substituents, whether
identical or not.
The halogen atom is exemplified by fluorine, chlorine, bromine and iodine,
preferably fluorine and chlorine. The cycloalkyl group is exemplified by
C.sub.3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl. The aryl group is exemplified by C.sub.6-10 aryl group
such as phenyl and naphthyl, and preferably a phenyl. With respect to the
amino group which may have an alkyl, alkenyl, cycloalkyl or aryl group as
a substituent, the alkyl group is exemplified by C.sub.1-4 alkyl groups
such as methyl, ethyl, propyl and isopropyl; the alkenyl group is
exemplified by C.sub.2-4 alkenyl group such as ethenyl, propenyl,
isopropenyl and butenyl; the cycloalkyl group is exemplified by C.sub.3-6
cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl; the aryl group is exemplified by C.sub.6-10 aryl group such as
phenyl and naphthyl, preferably a phenyl. Said amino group is preferably
an amino group which may be substituted by one to three C.sub.1-4 alkyl
groups (e.g., methyl, ethyl, etc.), such as amino, methylamino,
ethylamino, dimethylamino, trimethylamino and diethylamino. The optionally
halogenated alkoxy group is exemplified by C.sub.1-4 alkoxy group such as
methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,
propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy and
sec-butoxy, or such alkoxy group substituted for by 1 to 3 halogen atoms
(e.g., fluorine, chlorine). The acyl group is a C.sub.1-4 acyl group such
as formyl, acetyl, propionyl, butyryl or isobutyryl. The acyloxy group is
a C.sub.1-4 acyloxy group such as formyloxy, acetyloxy, propionyloxy,
butyryloxy or isobutyryloxy. The protecting group for the optionally
protected carboxyl group is exemplified by C.sub.1-4 alkyl groups such as
methyl, ethyl and t-butyl groups and C.sub.7-11 aralkyl group such as
benzyl. The alkylthio group is a C.sub.1-4 alkylthio group such as
methylthio, ethylthio, propylthio, isopropylthio or butylthio. The
alkylsulfonyl group is a C.sub.1-4 alkylsulfonyl group such as a
methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or
butylsulfonyl group.
Preferable example of substituents for the optionally substituted
hydrocarbon group include (i) halogen, (ii) cycloalkyl group, (iii) aryl
group, (iv) amino group which may have an alkyl, alkenyl, cycloalkyl or
aryl group as a substituent, (v) hydroxyl group, (vi) optionally
halogenated alkoxy group (vii) acyl group, (viii) acyloxy group, (ix)
cyano group, (x) optionally protected carboxyl group and (xi) carbamoyl
group, and the term of (i) to (xi) is the same meaning described
hereinabove.
More preferable examples of the substituent include the follows (1) to (3):
(1) (i) C.sub.3-6 cycloalkyl group such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and so on,
(ii) C.sub.6-10 aryl group such as phenyl, naphthyl and so on,
(iii) amino group which may be substituted by one to three C.sub.1-4 alkyl
groups, such as amino, methylamino, ethylamino, dimethylamino,
trimethylamino, diethylamino and so on,
(iv) carboxyl group which may be substituted by a C.sub.1-4 alkyl, such as
carboxyl, carboxylmethyl, carboxylethyl and so on,
(2) halogen such as fuluoro, chloro, buromo and so on,
(3) (i) carboxyl, (ii) C.sub.1-4 alkyl-carbonyl such as carboxymethyl,
carboxyethyl, etc. or (iii) mono, di- or tri C.sub.1-4 alkylamino such as
amino, methylamino, dimethylamino, trimethylamino, etc.
Further, the hydrocarbon group are also preferable a C.sub.1-6 alkyl group,
C.sub.3-6 cycloalkyl group, a C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl group,
preferably a C.sub.1-6 alkyl group. The C.sub.1-6 alkyl group mentioned
above includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and so on. Preferred are
C.sub.1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl and so on. The C.sub.3-6 cycloalkyl group
may for example be cyclopropyl, cyclopentyl or cyclohexyl and so on. The
C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl group includes, among others,
cyclopropylmethyl and cyclopropylethyl and so on.
The substituent group(s) of the hydrocarbon group include halogen atom
(e.g. fluoro, chloro, bromo, iodo, etc.), nitro, cyano, hydroxyl,
C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy, propyloxy, butyloxy,
isopropyloxy, etc.), C.sub.1-4 alkylthio group (e.g. methylthio,
ethylthio, propylthio etc.), amino, mono-, di or tri-C.sub.1-4 alkylamino
group (e.g. methylamino, ethylamino, propylamino, dimethylamino,
diethylamino, trimethylamino etc.), cyclic amino group (e.g. 5- to
9-membered cyclic amino group which may contain 1 to 3 hetero-atoms such
as oxygen and sulfur in addition to nitrogen as ring-constituent members,
such as pyrrolidino, piperidino, morpholino, etc.), C.sub.1-4
alkyl-carbonylamino group (e.g. acetylamino, propionylamino, butyrylamino,
etc.), C.sub.1-4 alkylsulfonylamino group (e.g. methylsulfonylamino,
ethylsulfonylamino, etc.), C.sub.1-4 alkoxy-carbonyl group (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl,
C.sub.1-6 alkyl-carbonyl group (e.g. methylcarbonyl, ethylcarbonyl,
propylcarbonyl, etc.), carbamoyl, mono- or di-C.sub.1-4 alkyl-carbamoyl
group (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), C.sub.1-6
alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl,
etc.), phenyl, C.sub.1-3 alkoxyphenyl (e.g. methoxyphenyl, ethoxyphenyl,
etc.) and so on. 1 to 5, preferably 1 or 2, species of these substituents
may be present.
Preferable examples of substituents hereinabove include a hydroxyl group, a
C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.), an amino
group, a mono- or di-C.sub.1-4 alkylamino group (e.g. methylamino,
ethylamino, dimethylamino, diethylamino, etc.), a C.sub.1-4
alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, etc.), a carboxyl group, a carbamoyl group, a phenyl
group and so on.
Specially preferable examples of substituents are a carboxyl group and a
carbamoyl group.
The optionally substituted hydroxyl group described hereinabove includes a
hydroxyl group, a C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy, propoxy,
isopropoxy, butoxy, t-butoxy, etc.), a C.sub.6-10 aryloxy group (e.g.
phenoxy, naphthyloxy, etc.), a C.sub.1-4 alkyl-carbonyloxy (e.g.
formyloxy, acethyoxy, propyonyloxy, etc.) and a C.sub.6-10
aryl-carbonyloxy group (e.g. benzoyloxy, naphthoyloxy, etc.).
Preferable examples are a hydroxyl group and a C.sub.1-4 alkoxy group (e.g.
methoxy, ethoxy, propoxy, isopropoxy, etc.)
These groups may be substituted, and the substituents include the same one
as the substituents of the hydrocarbon group hereinabove, preferably a
halogen atom (e.g. fluoro, chloro, bromo, etc.).
The substituted hydroxyl group include a C.sub.1-4 alkoxy group (e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc.), a
C.sub.6-10 aryloxy group (e.g. phenoxy, naphthyloxy, etc.), a C.sub.1-4
alkyl-carbonyloxy (e.g. formyloxy, acethyoxy, propyonyloxy, etc.), a
C.sub.6-10 aryl-carbonyloxy group (e.g. benzoyloxy, naphthoyloxy, etc.).
Preferable examples are a C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy,
propoxy, etc.). The substituents of a substituted hydroxyl group include
the same one as the substituents of the hydrocarbon group hereinabove and
so on, preferably a halogen atom (e.g. fluoro, chloro, bromo, etc.).
The halogen atom includes a fluorine, a chlorine, a bromine and so on.
The optionally substituted amino group includes an amino group which may be
substituted by one to three substituents selected from the group
consisting of (i) C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl,
isopropyl, etc.), (ii) C.sub.1-4 alkyl-carbonyl (e.g. acetyl, propyonyl,
butynyl, etc.), (iii) C.sub.1-4 alkoxy-carbonyl group (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), (iv) halogen
(e.g. fluoro, chloro, etc.), (v) phenyl, (vi) C.sub.1-4 alkyl-phenyl (e.g.
4-methylphenyl, 3-methylphenyl, 2-methylphenyl, etc.), (vii) halogenated
phenyl (e.g. 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, etc.) and
(viii) C.sub.1-4 alkoxy-phenyl (e.g. 4-methoxyphenyl, 3-methoxyphenyl,
2-methoxyphenyl, etc.) and so on.
Preferable examples of an optionally substituted amino group include an
amino group or a mono- or di-C.sub.1-4 alkylamino group (e.g. methylamino,
ethylamino, propylamino, dimethylamino, diethylamino, etc.).
The optionally substituted hydrocarbon group of the mercapto group
substituted by an optionally substituted hydrocarbon group are used the
same one as defined hereinabove. Preferable examples of the mercapto group
substituted by an optionally substituted hydrocarbon group include a
C.sub.1-4 alkylthio (e.g. methylthio, ethylthio, propylthio, etc.), and so
on.
Preferable examples of R.sup.1 include (i) a hydrogen atom and (ii) a
C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl, etc.) which may be
substituted by (a) a mono-, di- or tri- C.sub.1-4 alkylamino group (e.g.
methylamino, ethylamino, propylamino, dimethylamino, trimethylamino,
etc.), (b) a C.sub.1-4 alkoxy-carbonyl group (e.g. methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, etc.), (c) a carbamoyl group or (d) a
carboxyl group.
More preferable examples of R.sup.1 are a C.sub.1-4 alkyl group (e.g.
methyl, ethyl, propyl, etc.).
Preferable example of R.sup.2 and R.sup.2a is a hydrogen atom
Preferable examples of R.sup.3 include (i) a hydrogen atom, (ii) a halogen
atom (e.g. fluoro, chloro, bromo, etc.), a C.sub.1-4 alkoxy group (e.g.
methoxy, ethoxy, propoxy, etc.), a C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl, etc.), a C.sub.1-4 alkylthio group (e.g. methylthio,
ethylthio, etc.) and a mono- or di-C.sub.1-4 alkylamino, (e.g.
methylamino, ethylamino, dimethylamino, diethylamino, etc.); and (iii) a
halogen atom (e.g. fluoro, chloro etc.) and mono-C.sub.1-4 alkylamino
(e.g. methylamino, ethylamino, etc.).
Preferable examples of R.sup.4 include (i) a hydrogen atom and (ii) a
C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl, etc.), a hydroxyl group
and halogen atom (e.g. fluoro, chloro, etc.).
Preferable examples of R.sup.5 include (i) a hydrogen atom and (ii) a
C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl, etc.).
With respect to the above formula, either X or Y represents --NR.sup.1 --
(R.sup.1 represents a hydrogen atom, an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group or an optionally
substituted amino group), --O-- or --S--, the other representing --CO--,
--CS-- or --C(R.sup.2)R.sup.2a -- (R.sup.2 and R.sup.2a independently
represent a hydrogen atom or an optionally substituted hydrocarbon group),
or ether X or Y represents --N.dbd., the other representing .dbd.CR.sup.3
-- (R.sup.3 represents a hydrogen atom, a halogen atom, an optionally
substituted hydrocarbon group, an optionally substituted amino group, a
substituted hydroxyl group or a mercapto group substituted by an
optionally substituted hydrocarbon group).
Preferable examples of X and Y (--X--Y--) include the following:
(i) either X or Y represents --NR.sup.1 -- or --O--, the other representing
--CO--, --CS-- or --C(R.sup.2)R.sup.2a -- (R.sup.1, R.sup.2 and R.sup.2a
represent the same meanings as defined hereinabove),
(ii) either X or Y represents --N.dbd., the other representing
.dbd.CR.sup.3 -- (R.sup.3 represents the same meaning as defined
hereinabove),
(iii) --NR.sup.1 --CO--, --NR.sup.1 --CH.sub.2 --, --CONR.sup.1 --,
--O--CO--, --CO--O--, --N.dbd.CR.sup.3 -- and --CR.sup.3 .dbd.N-- (R.sup.1
and R.sup.3 represents the same meanings as defined hereinabove),
(iv) --N(CH.sub.3)--CO--, --N(C.sub.2 H.sub.5)--CO--,
--N(CH.sub.3)--CH.sub.2 --, --N(C.sub.2 H.sub.5)--CH.sub.2, --CO--
N(CH.sub.3), --CO--N(C.sub.2 H.sub.5)--, --O--CO--, --CO--O--
--N.dbd.CH--, --N.dbd.C(CH.sub.3)--, --N.dbd.C(OCH.sub.3)--, --N.dbd.CCl,
--N.dbd.C(NHCH.sub.3)--, --CH.dbd.N--, --C(Cl).dbd.N--,
--C(OCH.sub.3).dbd.N-- and --C(NHCH.sub.3).dbd.C--,
(v) --CONR.sup.1 -- and --NR.sup.1 --CO-- (R.sup.1 represents the same
meanings as defined hereinabove)
(vi) --O--CO--
(vii) --CO--O--
(viii) --NR.sup.1 --C(R.sup.2)R.sup.2a -- and --C(R.sup.2)R.sup.2a
--NR.sup.1 -- (R.sup.1, R.sup.2 and R.sup.2a represent the same meaning as
defined hereinabove),
(ix) --N.dbd.CR.sup.3 -- (R.sup.3 represents the same meaning as defined
hereinabove),
(x) --CS--NR.sup.1 -- (R.sup.1 represents the same meaning as defined
hereinabove).
With respect to the above formula, ........ represents a single or double
bond; (i) when ........ adjacent to Z is a single bond, Z represents
##STR34##
(R.sup.4 represents a hydrogen atom, a hydroxyl group or an optionally
substituted hydrocarbon group) or a nitrogen atom, or (ii) when ........
adjacent to Z is a double bond, Z represents a carbon atom.
Preferable examples of ........ and Z include the following:
i) ........ on the ring A is a double bond,
ii) ........ on the ring C is a single bond, and Z is
##STR35##
(R.sup.4 represents the same meanings as defined hereinabove), iii)
........ on the ring C is a single bond, and Z is a nitrogen atom,
iv) ........ on the ring C is a double bond, and Z is a carbon atom.
With respect to the above formula, D represent a C.sub.1-3 alkylene group
which may be substituted by an oxo or thioxo group, or D and R.sup.1,
taken together, may form 5- to 7-membered ring which may be substituted by
an oxo or thioxo group.
The C.sub.1-3 alkylene group includes --CH.sub.2 --, --CH.sub.2 CH.sub.2
--, --CH.sub.2 CH.sub.2 CH.sub.2 -- and --CH(CH.sub.3)--CH.sub.2 -- and so
on.
D includes --CO--, --CS--, --CH.sub.2 --, --CH.sub.2 CH.sub.2 --,
--CH.sub.2 CO--, --CH.sub.2 CS--, --CH.sub.2 CH.sub.2 CO-- and --CH.sub.2
CH.sub.2 CS-- and so on.
Preferable examples of D include
(i) a C.sub.1-3 alkylene group which may be substituted by an oxo group,
(ii) --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CO--, --CH.sub.2 CO-- and
--CH.sub.2 CH.sub.2 CO--, (iii) --CO--, (iv) --CH.sub.2 CO-- and
--CH.sub.2 CH.sub.2 CO--, and (v) --CH.sub.2 -- and --CH.sub.2 CH.sub.2
--.
Preferable examples of the compounds (I) and (I') wherein the 5- to
7-membered ring is formed by D and Y include compounds of the formula:
##STR36##
wherein ring K.sup.a may be substituted by an oxo or thioxo group; h
represents an integer of 3 to 5; and the other symbols represent the same
meaning as defined hereinabove, more preferably the compounds of the
formula:
##STR37##
wherein ring K.sup.b may be substituted by an oxo group; and the other
symbols represent the same meaning as defined hereinabove.
With respect to the above formula, E represents --NR.sup.5 -- (R.sup.5
represents a hydrogen atom or an optionally substituted hydrocarbon
group), --O-- or --S(O)n-- (n is 0, 1 or 2), or R.sup.5 and Y, taken
together, may form 5- to 7-membered ring which may be substituted by an
oxo or thioxo group.
Preferable examples of the compounds (I) and (I') wherein the 5- to
7-membered ring combined R.sup.5 and Y include also compounds of the
formula:
##STR38##
wherein the ring K.sup.c may be substituted by an oxo or thioxo group; i
represents an integer of 1 to 3, the total carbon number of E and
--(CH.sub.2)i-- being 3 to 5; and the other symbols represent the same
meanings as defined hereinabove, preferably compound of the formula:
##STR39##
wherein E.sup.a and M represent --CH.sub.2 -- or --CO--; and the other
symbols represent the same meanings as defined hereinabove.
Preferable examples of E include --NR.sup.5 -- (R5 represents the same
meaning as defined hereinabove) and --O--, more preferably --NR.sup.5 --
(R.sup.5 represents the same meaning as defined hereinabove).
Preferable examples of G include the following:
(i) a bond,
(ii) a C.sub.1-3 alkylene group such as methylene, ethylene, propylene,
etc.
Preferable examples of D, E and G include the follow:
(i) D is --CO--; E is --NR.sup.5 -- (R.sup.5 represents the same meaning as
defined hereinabove); G is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --,
(ii) D is --CO--; E is --NR.sup.5 -- (R.sup.5 represents the same meaning
as defined hereinabove); G is a bond,
(iii) D is --CH.sub.2 CO-- or --CH.sub.2 CH.sub.2 CO--; E is --NR.sup.5 --
(R.sup.5 represent the same meaning as defined herein); G is a bond,
(iv) D is --CH.sub.2 CO-- or --CH.sub.2 CH.sub.2 CO--; E is --NR.sup.5 --
(R.sup.5 represent the same meaning as defined hereinabobe); G is
--CH.sub.2 -- or --CH.sub.2 CH.sub.2 --,
(v) D is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --; E is --O--; G is
--CH.sub.2 -- or --CH.sub.2 CH.sub.2 --,
(vi) D is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --; E is --NR.sup.5 --
(R.sup.5 represent the same meaning as defined herein); G is --CH.sub.2 --
or --CH.sub.2 CH.sub.2 --,
(vii) D is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --; E is --S-- or --SO--; G
is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --.
In the above formula, Ar represents an optionally substituted aryl group or
an optionally substituted heterocyclic group. The aryl group in the
"optionally substituted aryl group" represented by Ar, is preferably a
C.sub.6-10 aryl group such as phenyl or naphthyl or the like, with greater
preference given to a phenyl group etc. The aryl group represented by Ar
may have one to five substituents, preferably one to three substituents,
whether identical or not. These substituents may be located at any
position of the ring. Such substituents include an optionally halogenated
C.sub.1-4 alkyl group (e.g., methyl, chloromethyl, difluoromethyl,
trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, butyl), C.sub.1-4
alkyl group substituted by an amino group (e.g., aminomethyl,
2-aminoethyl, etc.), C.sub.1-4 alkyl group substituted by a mono- or
di-C.sub.1-4 alkylamino group (e.g., methylaminomethyl,
dimethyl-aminomethyl), C.sub.1-4 alkyl group substituted by a carboxyl
group (e.g., carboxymethyl, carboxyethyl), C.sub.1-4 alkyl group
substituted by a C.sub.1-4 alkoxycarbonyl group (e.g.,
methoxycarbonylethyl, ethoxycarbonylethyl), C.sub.1-4 alkyl group
substituted by a hydroxyl group (e.g., hydroxymethyl, hydroxyethyl),
C.sub.1-4 alkyl group substituted by a C.sub.1-4 alkoxycarbonyl group
(e.g., methoxymethyl, methoxyethyl, ethoxyethyl), C.sub.3-6 cycloalkyl
group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen
atom (e.g., fluorine, chlorine, bromine, iodine), nitro group, cyano
group, hydroxyl group, optionally halogenated C.sub.1-4 alkoxy group
(e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, propyloxy, butyloxy, isopropyloxy), optionally
halogenated C.sub.1-4 alkylthio group (e.g., methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio), amino group, mono- or di-C.sub.1-4 alkylamino
group (e.g., methylamino, ethylamino, propylamino, dimethylamino,
diethylamino), cyclic amino group (e.g., 5- to 9-membered cyclic amino
group which may have one to three hetero atoms such as oxygen and sulfur
atoms in addition to nitrogen atoms, specifically pyrrolidino, piperidino,
morpholino), C.sub.1-4 alkylcarbonylamino group (e.g., acetylamino,
propionylamino, butylylamino), aminocarbonyloxy group, mono- or di-
C.sub.1-4 alkylaminocarbonyloxy group (e.g., methylaminocarbonyloxy,
ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy),
C.sub.1-4 alkylsulfonylamino group (e.g., methylsulfonylamino,
ethylsulfonylamino, propylsulfonylamino), C.sub.1-4 alkoxy-carbonyl group
(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isobutoxycarbonyl), benzyloxycarbonyl group, carboxyl group, C.sub.1-6
alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl),
C.sub.3-6 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl), carbamoyl
group, mono- or di-C.sub.1-4 alkylcarbamoyl group (e.g., methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl,
dibutylcarbamoyl) and C.sub.1-6 alkylsulfonyl group (e.g., methylsulfonyl,
ethylsulfonyl, propylsulfonyl). In addition, the below-described
"optionally substituted heterocyclic group," represented by Ar, may be
used as such as a substituent for the aryl group. This optionally
substituted heterocyclic group is exemplified by 5- or 6-membered aromatic
mono-heterocyclic group (e.g., furyl, thienyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) which
may be substituted by one to three substituents such as those selected
from the group consisting of optionally halogenated C.sub.1-4 alkyl group
(e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl,
trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,
3,3,3-trifluoropropyl, butyl), C.sub.3-6 cycloalkyl group (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen atom (e.g.,
fluorine, chlorine, bromine, iodine), hydroxyl group, optionally
halogenated C.sub.1-4 alkoxy group (e.g., methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propyloxy, butyloxy,
isopropyloxy), optionally halogenated C.sub.1-4 alkylthio group (e.g.,
methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
propylthio, isopropylthio, butylthio), amino group, mono- or di-C.sub.1-4
alkylamino group (e.g., methylamino, ethylamino, propylamino,
dimethylamino, diethylamino), C.sub.1-4 alkoxy-carbonyl group (e.g.,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl),
carboxyl group and C.sub.1-6 alkyl-carbonyl group (e.g., methylcarbonyl,
ethylcarbonyl, butylcarbonyl).
Preferable examples of substituents of Ar include optionally halogenated
C.sub.1-4 alkyl group (e.g., methyl, chloromethyl, difluoromethyl,
trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl), halogen
atom (e.g., fluorine, chlorine, bromine), nitro group, hydroxyl group,
optionally halogenated C.sub.1-4 alkoxy group (e.g., methoxy,
difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy), amino
group, C.sub.1-4 alkyl group substituted by a mono-or di-C.sub.1-4
alkylamino group (e.g., methylaminomethyl, dimethylaminomethyl,
2-methylaminoethyl, 2-dimethylaminoethyl.), mono- or di-C.sub.1-4
alkylamino group (e.g., methylamino, ethylamino, dimethylamino,
diethylamino), C.sub.1-4 alkoxy-carbonyl group (e.g., methoxycarbonyl,
ethoxycarbonyl), carboxyl group and carbamoyl group, and optionally
halogenated C.sub.1-4 alkyl group (e.g., methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
propyl, isopropyl), halogen atom (e.g., fluorine, chlorine, bromine) and
C.sub.1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy) are commonly used.
The heterocyclic group in the "optionally substituted heterocyclic group,"
represented by Ar, is exemplified by 5- to 9-membered, preferably 5- or
6-membered aromatic heterocyclic group which may have one to four,
preferably one or two hetero atoms such as nitrogen, oxygen and sulfur
atoms in addition to carbon atoms.
Such aromatic heterocyclic group include aromatic mono-heterocyclic group
such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl and aromatic condensed
heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo›b!thienyl,
indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl, benzoxazolyl,
1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl,
1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, naphthylizinyl, purinyl, pteridinyl,
carbazolyl, .alpha.-carbolinyl, .beta.-carbolinyl, .gamma.-carbolinyl,
acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl,
thianthrenyl, phenatholidinyl, phenathololinyl, indolizinyl,
pyrrolo›1,2-b!pyridazinyl, pyrazolo›1,5-a!pyridyl, imidazo›1,2-a!pyridyl,
imidazo›1,5-a!pyridyl, imidazo›1,2-b!pyridazinyl,
imidazo›1,2-a!pyrimidinyl, 1,2,4-triazolo›4,3-a!pyridyl and
1,2,4-triazolo›4,3-b!pyridazinyl.
Preferable examples of the heterocyclic group include 5- or 6-membered
heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl,
isoquinolyl, thiazolyl, thiadiazolyl and thiophenyl, with greater
preference given to furyl, thienyl, pyridyl, etc.
The substituent in the "optionally substituted heterocyclic group,"
represented by Ar, is exemplified by optionally halogenated C.sub.1-4
alkyl group(e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl,
trifluoromethyl, ethyl, 2,2-dibromoethyl, 2,2,2-triflu-oroethyl, propyl,
3,3,3-trifluoropropyl, butyl), C.sub.3-6 cycloalkyl group (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen atom (e.g.,
fluorine, chlorine, bromine, iodine), nitro group, cyano group, hydroxyl
group, optionally halogenated C.sub.1-4 alkoxy group (e.g., methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-triflu-oroethoxy, propyloxy, butyloxy, isopropyloxy), optionally
halogenated C.sub.1-4 alkylthio group (e.g., methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio), amino group, mono- or di-C.sub.1-4 alkylamino
group (e.g., methylamino, ethylamino, propylamino, dimethylamino,
diethylamino), cyclic amino group (e.g., 5- to 9-membered cyclic amino
groups which may have one to three hetero atoms such as oxygen and sulfur
atoms in addition to nitrogen atoms, specifically pyrrolidino, piperidino,
morpholino), C.sub.1-4 alkylcarbonylamino group (e.g., acetylamino,
propionylamino, butylylamino), aminocarbonyloxy group, mono- or
di-C.sub.1-4 alkylaminocarbonyloxy group (e.g., methylaminocarbony-loxy,
ethylaminocarbonyloxy, dimethylaminocarbonyloxy,
diethylaminocar-bonyloxy), C.sub.1-4 alkylsulfonylamino group (e.g.,
methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino), C.sub.1-4
alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isobutoxycarbonyl), carboxyl group, C.sub.1-6
alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl),
C.sub.3-6 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl), carbamoyl
group, mono- or di-C.sub.1-4 alkylcarbamoyl group (e.g., methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl,
dibutylcarbamoyl), C.sub.1-6 alkylsulfonyl group (e.g., methylsulfonyl,
ethylsulfonyl, propylsulfonyl), C.sub.3-6 cycloalkylsulfonyl group (e.g.,
cyclopentylsulfonyl, cyclohexylsulfonyl), phenyl, naphthyl, phenoxy,
benzoyl, phenoxycarbonyl, phenyl-C.sub.1-4 alkylcarbamoyl,
phenylcarbamoyl, phenyl-C.sub.1-4 alkyl-carbonylamino, benzoylamino,
phenyl-C.sub.1-4 alkylsulfonyl, phenylsulfonyl, phenyl-C.sub.1-4
alkylsulfinyl, phenyl-C.sub.1-4 alkylsulfonylamino and phenylsulfonylamino
group which may have one to four substituents (the substituent for each
phenyl group or naphthyl group is exemplified by C.sub.1-4 alkyl group
such as methyl, ethyl, propyl, butyl and isopropyl, C.sub.1-4 alkoxy group
such as methoxy, ethoxy, n-propyloxy, i-propyloxy and n-butyloxy, halogen
atom such as chlorine, bromine and iodine, hydroxyl group, benzyloxy
group, amino group, mono- or di-C.sub.1-4 alkylamino group as descried
above, nitro group and C.sub.1-6 alkylcarbonyl group as described above);
one to three selected from these substituents are used.
Of these substituents are preferred halogen atom (e.g., fluorine, chlorine,
bromine), optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
chloromethyl, difluoromethyl, trifluoromethyl, ethyl), C.sub.3-6
cycloalkyl group (e.g., cyclopropyl, cyclobutyl), hydroxyl group,
optionally halogenated C.sub.1-4 alkoxy group (e.g., methoxy,
difluoromethoxy, trifluoromethoxy, ethoxy), optionally halogenated
C.sub.1-4 alkylthio group (e.g., methylthio, ethylthio), amino group,
mono- or di-C.sub.1-4 alkylamino group (e.g., methylamino, ethylamino,
dimethylamino, diethylamino), C.sub.1-4 alkoxy-carbonyl group (e.g.,
methoxycarbonyl, ethoxycarbonyl) and carboxyl group, with greater
preference given to halogen atom (e.g., fluorine, chlorine), C.sub.1-4
alkyl group (e.g., methyl, ethyl), C.sub.3-6 cycloalkyl group (e.g.,
cyclopropyl, cyclobutyl), hydroxyl group, C.sub.1-4 alkoxy group (e.g.,
methoxy, ethoxy) and carboxyl group, etc.
Ar is preferably a phenyl group which may have one to three substituents
selected from the group consisting of halogen atom (e.g., fluorine,
chlorine), optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, propyl,
isopropyl) and optionally halogenated C.sub.1-4 alkoxy group (e.g.,
methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,
propoxy, isopropoxy). Also preferred are 5- or 6-membered heterocyclic
groups (e.g., furyl, pyridyl, thienyl, thiazolyl, thiadiazolyl) which have
one to three hetero atoms (e.g., nitrogen atoms, oxygen atoms, sulfur
atoms) in addition to carbon atoms and which may be substituted by
optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl, ethyl), C.sub.1-4 alkoxy group (e.g., methoxy, ethoxy,
propoxy) or C.sub.3-6 cycloalkyl group (e.g., cyclopropyl).
Ar is preferably a phenyl group which may be substituted by one to three
substituents selected from the group consesting halogen (e.g., chlorine,
fluorine), optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl ethyl, isopropyl), optionally halogenated C.sub.1-4 alkoxy
group (e.g., methoxy, trifluoromethoxy, ethoxy), di-C.sub.1-4 alkylamino
group (e.g., dimethylamino), C.sub.1-3 acyloxy group (e.g., acetoxy) and
hydroxyl group, specifically a phenyl group which may be substituted for
and which is represented by formula:
##STR40##
wherein J.sup.1, J.sup.2 and J.sup.3, whether identical or not,
independently represent hydrogen, a halogen (e.g., chlorine, fluorine), an
optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl ethyl, isopropyl), an optionally halogenated C.sub.1-4
alkoxy group (e.g., methoxy, trifluoromethoxy, ethoxy) or a di-C.sub.1-4
alkylamino group (e.g., dimethylamino), or by formula:
##STR41##
wherein J.sup.4, J.sup.5 and J.sup.6, whether identical or not,
independently represent hydrogen, an optionally halogenated C.sub.1-4
alkyl group (e.g., methyl, trifluoromethyl isopropyl, t-butyl), a
C.sub.1-3 acyloxy group (e.g., acetoxy) or a hydroxyl group. More
preferably, for example, there may be used a phenyl group which may be
substituted and which is represented by the above formulas (J.sup.a) and
(J.sup.b) wherein:
(1) J.sup.1, J.sup.2 and J.sup.3, whether identical or not, independently
represent halogen, an optionally halogenated C.sub.1-4 alkyl group or an
optionally halogenated C.sub.1-4 alkoxy group,
(2) J.sup.1 and J.sup.2, whether identical or not, independently represent
a halogen, an optionally halogenated C.sub.1-4 alkyl group or an
optionally halogenated C.sub.1-4 alkoxy group, J.sup.3 being hydrogen,
(3) J.sup.1 and J.sup.3, whether identical or not, independently represent
a halogen, an optionally halogenated C.sub.1-4 alkyl group or an
optionally halogenated C.sub.1-4 alkoxy group, J.sup.2 being hydrogen,
(4) J.sup.1 and J.sup.3 are hydrogen, J.sup.2 being a halogen,
(5) J.sup.4 is a di-C.sub.1-4 alkylamino group, J.sup.5 and J.sup.6 being
hydrogen,
(6) J.sup.4 and J.sup.6 are hydrogen, J.sup.5 being a di-C.sub.1-4
alkylamino group, or
(7) J.sup.4 and J.sup.6, whether identical or not, independently represent
an optionally halogenated C.sub.1-4 alkyl group or an optionally
halogenated C.sub.1-4 alkoxy group, J.sup.5 being a C.sub.1-3 acyloxy
group or a hydroxyl group.
In the above (1) to (7), the optionally halogenated C.sub.1-4 alkyl group
includes methyl, trifluoromethyl, ethyl, etc.; the optionally halogenated
C.sub.1-4 alkoxy group includes methoxy, trifluoromethoxy, ethoxy, etc.;
the halogen atom includes fluoro, chloro, etc.; the di-C.sub.1-4
alkylamino group includes N,N-dimethylamino, N,N-diethylamino, etc.; the
C.sub.1-3 acyloxy group includes formyloxy, acetoxy, etc.
More preferably for Ar, for example, there may be used a penyl group which
may be substituted and which is represented by the above formulas
(J.sup.a) and (J.sup.b) wherein:
(a) J.sup.1, J.sup.2 and J.sup.3 are all fluorine, a methyl or methoxy
group,
(b) J.sup.1 and J.sup.2 are both chlorine, a fluorine, isopropyl or methoxy
group, J.sup.3 being hydrogen,
(c) J.sup.1 and J.sup.3 are both chlorine, fluorine, a methyl, ethyl,
isopropyl or methoxy group, J.sup.2 being hydrogen,
(d) J.sup.1 is an isopropyl group, J.sup.2 being hydrogen, J.sup.3 being a
methyl group,
(e) J.sup.1 and J.sup.3 are hydrogen, J.sup.2 being chlorine,
(f) J.sup.1 and J.sup.2 are methyl, trifluoromethyl group, J.sup.3 is a
hydrogen,
(g) J.sup.4 is an N,N-dimethylamino group, J.sup.5 and J.sup.6 being
hydrogen,
(h) J.sup.4 and J.sup.6 are hydrogen, J.sup.5 being an N,N-dimethylamino
group,
(i) J.sup.4 and J.sup.6 are both a methyl, trifluoromethyl or isopropyl
group, J.sup.5 being an acetoxy group, or
(j) J.sup.4 and J.sup.6 are both a methyl, trifluoromethyl, isopropyl or
t-butyl group, J.sup.5 being a hydroxyl group.
With respect to the above formulas, two isomers exist with different
relative configurations of positions 3 and 4 on the condensed ring,
provided that ........ is a single bond and Z is
##STR42##
(R.sup.4 has the same definitions as above), each of which isomers
involves two isomers with different absolute configurations. Provided that
........ is a single bond and Z is a nitrogen atom, there are two isomers
with different absolute configurations of position 3. The present
invention includes these isomers and mixtures thereof. In this context,
the position 3 of the condensed ring indicates the position of the carbon
atom to which the side is bond, the position 4 including the position of
Z.
Preferable examples of the compounds (I) and (I') include compounds of the
formula:
##STR43##
wherein rings A', B' and J independently represent an optionally
substituted benzene ring; either X' or Y' represents --NR.sup.1a --
(R.sup.1a represents an optionally substituted hydrocarbon group), --O--
or --S--, the other representing --CO--, --CS-- or --C(R.sup.2)R.sup.2a --
(R.sup.2 and R.sup.2a independently represent a hydrogen atom or an
optionally substituted hydrocarbon group), or either X' or Y' represents
--N.dbd., the other representing .dbd.CR.sup.3a -- (R.sup.3a represents a
hydrogen atom, an optionally substituted hydrocarbon group or --OR wherein
R represents an optionally substituted hydrocarbon group; ........
represents a single or double bond; (i) when ........ is a single bond, Z'
represents
##STR44##
(R.sup.4a represents a hydrogen atom or an optionally substituted
hydrocarbon group) or a nitrogen atom, or (ii) when ........ is a double
bond, Z represents a carbon atom; .alpha. represents 0, 1 or 2, provided
that when --X'--Y'-- is --O--CO--, .alpha. represents 1 or 2, or a salt
thereof.
And, the compound (VI) can be produced by a process which comprises
reacting a compound of the formula:
##STR45##
wherein the symbols have the same definitions as above, or, a salt or
reactive derivative thereof with a compound represented by general
formula:
##STR46##
wherein the symbols have the same definitions as above, or a salt thereof.
Further, a compound represented by general formula:
##STR47##
wherein either X" or Y" represents --NR.sup.1b -- (R.sup.1b represents a
hydrogen atom or an optionally substituted hydrocarbon group), --O-- or
--S--, the other representing --CO--, --CS-- or --C(R.sup.2)R.sup.2a --
(R.sup.2 and R.sup.2a have the same definitions as above), or either X" or
Y" represents --N.dbd., the other representing .dbd.CR.sup.3a -- (R.sup.3a
has the same definition as above), the other symbols having the same
definitions as above, unexpectedly exhibits potent ACAT-inhibitory action
and is useful as a safe blood cholesterol lowering agent and
arteriosclerosis therapeutic composition.
Preferable examples of the above symbols include the following:
(1) the substituent of the ring A', B' and J is (i) a halogen, (ii) an
optionally halogenated C.sub.1-6 alkyl group, (iii) a C.sub.1-6 alkoxy
group, (iv) a hydroxyl group, (v) an amino group which may be substituted
by C.sub.1-4 alkyl groups or (vi) a C.sub.1-3 acyloxy group,
(2) the ring A' is a benzene ring which may be substituted by one to four
substituents selected from the group consisting of halogen, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group and halogeno-C.sub.1-4 alkyl group,
(3) the ring A' is an optionally substituted benzene ring which is
represented by the formula:
##STR48##
wherein A.sup.1a, A.sup.2a and A.sup.3a, whether identical or not,
independently represent hydrogen, a halogen, a C.sub.1-4 alkyl group, a
C.sub.1-4 alkoxy group or a halogeno-C.sub.1-4 alkyl group,
(4) the ring B' is benzene ring which may be substituted by one to four
substituents selected from the group consisting of halogen, C.sub.1-4
alkyl group and C.sub.1-4 alkoxy group,
(5) the ring B' is an optionally substituted benzene ring which is
represented by the formula:
##STR49##
wherein B.sup.1b, B.sup.2b and B.sup.3b, whether identical or not,
independently represent hydrogen, a halogen, a C.sub.1-4 alkyl group or a
C.sub.1-4 alkoxy group,
(6) the ring J is an optionally substituted benzene ring by one to four
substituents selected from the group consisting of halogen, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group di-C.sub.1-4 alkylamino group,
C.sub.1-3 acyloxy group and hydroxyl group,
(7) the ring J is an optionally substituted benzene ring which is
represented by the formula:
##STR50##
wherein J.sup.1a, J.sup.2a and J.sup.3a, whether identical or not,
independently represent hydrogen, a halogen, a C.sub.1-4 alkyl group, a
C.sub.1-4 alkoxy group or a di-C.sub.1-4 alkylamino group or by the
formula:
##STR51##
wherein J.sup.4a, J.sup.5a and J.sup.6a, whether identical or not,
independently represent hydrogen, a C.sub.1-4 alkyl group, a C.sub.1-3
acyloxy group or a hydroxyl group,
(8) the --X'--Y'-- is the formula --NR.sup.1a --CO--, --NR.sup.1a
--C(R.sup.2)R.sup.a --, --N .dbd.CR.sup.3a --, --O--CO-- or --CO--O-- (in
these formulas the symbols have the same definitions as above),
(9) .alpha. is 1,
In the above in (1) to (9), the halogen includes fluoro, chloro, etc; the
optionally halogenated C.sub.1-6 alkyl group includes methyl,
trifluoromethyl, ethyl, propyl, etc; the C.sub.1-6 alkoxy includes
methoxy, ethoxy, propoxy, butoxy; the amino group which may be substituted
by one or two C.sub.1-4 alkyl groups includes amino, methylamino,
dimethylamino, etc; the C.sub.1-3 acyloxy includes formyloxy, acetoxy; the
C.sub.1-4 alkyl includes methyl, ethyl, propyl; the C.sub.1-4 alkoxy
includes methoxy, ethoxy, propoxy; the halogeno-C.sub.1-4 alkyl group
includes trifluoromethyl; the di-C.sub.1-4 alkylamino includes
N,N-dimethylamino.
With respect to the above formulas, rings A', B' and J independently
represent a benzene ring which may have substituents. Such substituents
include halogen (e.g., fluorine, chlorine, bromine and iodine, preferably
chlorine, fluorine etc.), optionally halogenated alkyl group, optionally
halogenated alkoxy group, optionally halogenated alkylthio group,
C.sub.1-7 acylamino group (e.g., formylamino, acetylamino, propionylamino,
butyrylamino, benzoylamino), amino group which may be substituted by one
or two C.sub.1-4 alkyl groups (e.g., amino, methylamino, ethylamino,
propylamino, dimethylamino, methylethylamino, methylpropylamino),
C.sub.1-3 acyloxy group (e.g., formyloxy, acetoxy, propionyloxy), hydroxyl
group, cyano group and carboxyl group.
Examples of the optionally halogenated alkyl group include straight-chain
or branched alkyl groups having 1 to 6 carbon atoms and such alkyl groups
substituted for by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine
and iodine, preferably chlorine, bromine etc.). Specifically, commonly
used alkyl groups include methyl, chloromethyl, difluoromethyl,
trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,
isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
5,5,5-trifluoropentyl, 4-trifluoromethyl-butyl, hexyl,
6,6,6-trifluorohexyl and 5-trifluoromethylpentyl. Preferably used are
straight-chain or branched alkyl groups having 1 to 4 carbon atoms such as
methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,
ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl,
isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl and tert-butyl, or such alkyl groups substituted for by 1 to 3
of the above-mentioned halogen atoms.
Examples of the optionally halogenated alkoxy group and the optionally
halogenated alkylthio group include alkoxy groups which may be substituted
for by halogen and alkylthio groups which may be substituted for by
halogen, resulting from binding of either the above-exemplified alkyl
group or such alkyl group substituted for by halogen and either an oxygen
atom or a sulfur atom, respectively.
Examples of the optionally halogenated alkoxy group include straight-chain
or branched alkoxy groups having 1 to 6 carbon atoms or such alkoxy groups
substituted for by 1 to 5 of the above-mentioned halogen atoms.
Specifically, commonly used alkoxy groups include methoxy,
difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy,
isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy
and hexyloxy. Preferably used are linear or branched alkoxy groups having
1 to 4 carbon atoms such as methoxy, difluoromethoxy, trifluoromethoxy,
ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,
4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy, or such alkoxy groups
substituted for by 1 to 3 of the above-mentioned halogen atoms.
Examples of the alkylthio group which may be substituted by halogen include
straight-chain or branched alkylthio groups having 1 to 6 carbon atoms or
such alkylthio groups substituted for by 1 to 5 of the above-mentioned
halogen atoms. Specifically, commonly used alkylthio groups include
methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio
and hexylthio. Preferably used are straight-chain or branched alkylthio
groups having 1 to 4 carbon atoms such as methylthio, difluoromethylthio,
trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio and
4,4,4-trifluorobutylthio, or such alkylthio groups substituted for by 1 to
3 of the above-mentioned halogen atoms.
Preferable substituents for ring A', B' and J include (i) halogen (e.g.
fluorine, chlorine, bromine), (ii) optionally halogenated C.sub.1-6 alkyl
group (e.g. methyl, trifluoromethyl, ethyl, propyl), (iii) C.sub.1-6
alkoxy group (e.g. methoxy, ethoxy, propoxy), (iv) hydroxyl group, (v)
amino group which may be substituted by one or two C.sub.1-4 alkyl groups
(e.g. methylamino, ethylamino, dimethylamino, diethylamino) and (vi)
C.sub.1-3 acyloxy group (e.g. formyloxy, acetoxy).
The substituent(s) for rings A', B' and J may be located at any position on
the ring. When two or more substituents are present, they may be identical
or not, the number of substituents being 1 to 4, preferably 1 to 3, more
preferably 1 or 2. Also, the adjacent carbons on ring A', B' or J may bind
with a group represented by --(CH.sub.2)l-- (l represents an integer of
from 3 to 5) to form a 5- to 7-membered ring; this case is included in the
desired above products.
Ring A' is preferably a benzene ring which may be substituted by one to
four substituents selected from the group consisting of halogen (e.g.,
chlorine), optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
ethyl, isopropyl, trifluoromethyl) and C.sub.1-4 alkoxy group (e.g.,
methoxy), specifically a benzene ring which may be substituted for and
which is represented by formula ›A!:
##STR52##
wherein A.sup.1a, A.sup.2a and A.sup.3a, whether identical or not,
independently represent hydrogen, a halogen (e.g., fluorine, chlorine), a
C.sub.1-4 alkyl group (e.g., methyl, ethyl, isopropyl), a C.sub.1-4 alkoxy
group (e.g., methoxy, ethoxy) or a halogeno-C.sub.1-4 alkyl group (e.g.,
trifluoromethyl). More preferably, for example, there may be used benzene
rings which may be substituted for and which is represented by the above
formula ›A! wherein:
(1) A.sup.1a, A.sup.2a and A.sup.3a are all hydrogen,
(2) A.sup.1a and A.sup.2a are both hydrogen, A.sup.3a being a halogen (e.g.
fluorine, chlorine), an optionally halogenated C.sub.1-4 alkyl group (e.g.
methoxy, ethoxy) or an optionally halogenated C.sub.1-4 alkoxy group (e.g.
methoxy, trifluoromethoxy, ethoxy),
(3) A.sup.1a is hydrogen, A.sup.2a and A.sup.3a, whether identical or not,
being independently a halogen (e.g. fluorine, chlorine), a C.sub.1-4 alkyl
group (e.g. methyl, ethyl) or a C.sub.1-4 alkoxy group (e.g. methoxy,
ethoxy), or
(4) A.sup.2a is hydrogen, A.sup.1a and A.sup.3a, whether identical or not,
being independently a C.sub.1-4 alkyl group (e.g. methyl, ethyl).
More preferably for ring A', for example, there may be used optionally
substituted benzene rings which is represented by the above formula ›A!
wherein:
(a) A.sup.1a, A.sup.2a and A.sup.3a are all hydrogen,
(b) A.sup.1a and A.sup.2a are both hydrogen, A.sup.3a being chlorine, a
methyl, ethyl, isopropyl, methoxy or trifluoromethyl group,
(c) A.sup.1a is hydrogen, A.sup.2a and A.sup.3a being both a methyl or
methoxy group, or
(d) A.sup.2a is hydrogen, A.sup.1a and A.sup.3a being both a methyl group.
Ring B' is preferably an optionally substituted benzene ring by one to four
substituents selected from the group consisting of halogen (e.g., fluorine
chlorine,), optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl, ethyl) and C.sub.1-4 alkoxy group (e.g., methoxy,
ethoxy), specifically an optionally substituted benzene ring which is
represented by formula ›B!:
##STR53##
wherein B.sup.1b, B.sup.2b and B.sup.3b, whether identical or not,
independently represent hydrogen, a halogen (e.g., chlorine, fluorine), an
optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl, ethyl) or a C.sub.1-4 alkoxy group (e.g., methoxy,
ethoxy). More preferably, for example, there may be used benzene rings
which may be substituted for and which is represented by the above formula
›B! wherein:
(1) B.sup.1b, B.sup.2b and B.sup.3b are all hydrogen,
(2) B.sup.1b is halogen, an optionally halogenated C.sub.1-4 alkyl group
(e.g. methyl, trifluoromethyl, ethyl) or an optionally halogenated
C.sub.1-4 alkoxy group (e.g. methoxy, trifluoromethoxy, ethoxy), B.sup.2b
and B.sup.3b being both hydrogen,
(3) B.sup.1b is hydrogen, B.sup.2b and B.sup.3b, whether identical or not,
being independently an optionally halogenated C.sub.1-4 alkoxy group (e.g.
methoxy, trifluoromethoxy, ethoxy), or
(4) B.sup.1b, B.sup.2b and B.sup.3b, whether identical or not, are
independently an optionally halogenated C.sub.1-4 alkoxy group (e.g.
methoxy, trifluoromethoxy, ethoxy).
More preferably for ring B', for example, there may be used optionally
substituted benzene rings which is represented by the above formula ›B!
wherein:
(a) B.sup.1b, B.sup.2b and B.sup.3b are all hydrogen,
(b) B.sup.1b is chlorine, fluorine, a methyl, trifluoromethyl or methoxy
group, B.sup.2b and B.sup.3b being both hydrogen,
(c) B.sup.1b is hydrogen, B.sup.2b and B.sup.3b being both a methoxy group,
or
(d) B.sup.1b, B.sup.2b and B.sup.3b are all a methoxy group.
Ring J may be preferably a benzene ring which may be substituted by one to
four substituents selected from the group consisting of halogen (e.g.,
chlorine, fluorine, bromine), optionally halogenated C.sub.1-4 alkyl group
(e.g., methyl, trifluoromethyl, ethyl, isopropyl, t-butyl), C.sub.1-4
alkoxy group (e.g., methoxy), di-C.sub.1-4 alkylamino group (e.g.,
N,N-dimethylamino, N,N-diethylamino), C.sub.1-3 acyloxy group (e.g.,
formyloxy, acetoxy) and hydroxyl group, specifically an optionally
substituted benzene ring which is represented by formula ›J!:
##STR54##
wherein J.sup.1a, J.sup.2a and J.sup.3a, whether identical or not,
independently represent hydrogen, a halogen (e.g., chlorine, fluorine), an
optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl, ethyl, isopropyl), a C.sub.1-4 alkoxy group (e.g.,
methoxy) or a di-C.sub.1-4 alkylamino group (e.g., N,N-dimethylamino), or
by formula ›J'!:
##STR55##
wherein J.sup.4a, J.sup.5a and J.sup.6a, whether identical or not,
independently represent hydrogen, an optionally halogenated C.sub.1-4
alkyl group (e.g., methyl, trifluoromethyl, isopropyl, t-butyl), a
C.sub.1-3 acyloxy group (e.g., acetoxy) or a hydroxyl group. More
preferably, for example, there may be used a benzene ring which may be
substituted and which is represented by the above formula ›J! or ›J'!
wherein:
(1) J.sup.1a, J.sup.2a and J.sup.3a, whether identical or not,
independently represent halogen, a C.sub.1-4 alkyl group or a C.sub.1-4
alkoxy group,
(2) J.sup.1a and J.sup.2a, whether identical or not, independently
represent a halogen, a C.sub.1-4 alkyl group or a C.sub.1-4 alkoxy group,
J.sup.3a being hydrogen,
(3) J.sup.1a and J.sup.3a, whether identical or not, independently
represent a halogen, a C.sub.1-4 alkyl group or a C.sub.1-4 alkoxy group,
J.sup.2a being hydrogen,
(4) J.sup.1a and J.sup.3a are hydrogen, J.sup.2a being a halogen,
(5) J.sup.4a is a di-C.sub.1-4 alkylamino group, J.sup.5a and J.sup.6a
being hydrogen,
(6) J.sup.4a and J.sup.6a are hydrogen, J.sup.5a being a di-C.sub.1-4
alkylamino group, or
(7) J.sup.4a and J.sup.6a, whether identical or not, independently
represent a C.sub.1-4 alkyl group or a C.sub.1-4 alkoxy group, J.sup.5a
being a C.sub.1-3 acyloxy group or a hydroxyl group.
In the above (1) to (7), the C.sub.1-4 alkyl group includes methyl, ethyl,
propyl, isopropyl, etc.; the halogen atom includes fluorine, chlorine,
bromine, etc.; the C.sub.1-4 alkoxy group includes methoxy, ethoxy,
propoxy, etc.; the di-C.sub.1-4 alkylamino group includes
N,N-dimethylamino, N,N-diethylamino, etc.; the C.sub.1-3 acyloxy group
includes formyloxy, acetoxy, etc.
More preferably for ring J, for example, there may be used optionally
substituted benzene rings which is represented by the above formula ›J! or
›J'! wherein:
(a) J.sup.1a, J.sup.2a and J.sup.3a are all fluorine, a methyl or methoxy
group,
(b) J.sup.1a and J.sup.2a are both chlorine, a fluorine, isopropyl or
methoxy group, J.sup.3a being hydrogen,
(c) J.sup.1a and J.sup.3a are both chlorine, fluorine, a methyl, ethyl,
isopropyl or methoxy group, J.sup.2a being hydrogen,
(d) J.sup.1a is an isopropyl group, J.sup.2a being hydrogen, J.sup.3a being
a methyl group,
(e) J.sup.1a and J.sup.3a are hydrogen, J.sup.2a being chlorine,
(f) J.sup.4a is an N,N-dimethylamino group, J.sup.5a and J.sup.6a being
hydrogen,
(g) J.sup.4a and J.sup.6a are hydrogen, J.sup.5a being an N,N-dimethylamino
group,
(h) J.sup.4a and J.sup.6a are both a methyl or isopropyl group, J.sup.5a
being an acetoxy group, or
(i) J.sup.4a and J.sup.6a are both a methyl, isopropyl or t-butyl group,
J.sup.5a being a hydroxyl group.
With respect to the above formulas, R.sup.1a and R independently represent
an optionally hydrocarbon group; R.sup.1b, R.sup.2, R.sup.2a, R.sup.3a and
R.sup.4a independently represent a hydrogen atom or an optionally
substituted hydrocarbon group. Such hydrocarbon group include alkyl group,
alkenyl group, alkynyl group, cycloalkyl group and aryl group, preferably
a alkyl group.
The alkyl group is a straight-chain or branched one having 1 to 6 carbon
atoms such as methl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, hexyl, etc., preferably a straight-chain or
branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
The alkenyl group is one having 2 to 6 carbon atoms such as ethenyl,
propenyl, isopropenyl, butenyl, isobutenyl or sec-butenyl, preferably an
alkenyl group having 2 to 4 carbon atoms such as ethenyl, propenyl or
isopropenyl.
The alkynyl group is one having 2 to 6 carbon atoms such as ethynyl,
propynyl, isopropynyl, butynyl, isobutynyl or sec-butynyl, preferably an
alkenyl group having 2 to 4 carbon atoms such as ethynyl, propynyl or
isopropynyl.
The cycloalkyl group is a C.sub.3-8 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl, preferably a C.sub.3-6 cycloalkyl
group such as cyclopropyl or cyclobutyl.
The aryl group is one having 6 to 14 carbon atoms such as phenyl, naphthyl,
anthryl or phenanthryl, preferably an aryl group having 6 to 10 carbon
atoms such as phenyl or naphthyl, more preferably phenyl.
Examples of the substituent for the optionally substituted hydrocarbon
group include (i) halogen, (ii) cycloalkyl group, (iii) aryl group, (iv)
amino groups which may have an alkyl, alkenyl, cycloalkyl or aryl group as
a substituent, (v) hydroxyl group, (vi) optionally halogenated alkoxy
group, (vii) acyl group, (viii) acyloxy group, (ix) cyano group, (x)
optionally protected carboxyl group, (xi) carbamoyl group, (xii) mercapto
group, (xiii) alkylthio group, (xiv) sulfo group, and (xv) alkylsulfonyl
group.
The optionally substituted hydrocarbon group which may be substituted for
may be substituted for by 1 to 4, preferably 1 or 2 of the above-mentioned
substituents, whether identical or not.
The halogen atom is exemplified by fluorine, chlorine, bromine and iodine,
preferably fluorine and chlorine. The cycloalkyl group is exemplified by
C.sub.3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl. The aryl group is exemplified by C.sub.6-10 aryl groups
such as phonyl and naphthyl. With respect to the amino group which may
have an alkyl, alkenyl, cycloalkyl or aryl group as a substituent, the
alkyl group is exemplified by C.sub.1-4 alkyl group such as methyl, ethyl,
propyl and isopropyl; the alkenyl group is exemplified by C.sub.2-4
alkenyl group such as ethenyl, propenyl, isopropenyl and butenyl; the
cycloalkyl group is exemplified by C.sub.3-6 cycloalkyl group such as
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the aryl group is
exemplified by C.sub.6-10 aryl group such as phenyl and naphthyl. Said
amino group is preferably an amino group which may be substituted by a
C.sub.1-4 alkyl group, such as an amino, methylamino, ethylamino,
dimethylamino or diethylamino group. The optionally halogenated alkoxy
group is exemplified by C.sub.1-4 alkoxy group such as methoxy,
difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy,
isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy, or
such alkoxy group substituted for by 1 to 3 halogen atoms (e.g., fluorine,
chlorine). The acyl group is a C.sub.1-4 acyl group such as formyl,
acetyl, propionyl, butyryl or isobutyryl. The acyloxy group is a C.sub.1-4
acyloxy group such as formyloxy, acetyloxy, propionyloxy, butyryloxy or
isobutyryloxy. The protecting group for the optionally protected carboxyl
group is exemplified by C.sub.1-4 alkyl groups such as methyl, ethyl and
t-butyl groups and C.sub.7-11 -aralkyl group such as benzyl. The alkylthio
group is a C.sub.1-4 alkylthio group such as methylthio, ethylthio,
propylthio, isopropylthio or butylthio. The alkylsulfonyl group is a
C.sub.1-4 alkylsulfonyl group such as a methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl or butylsulfonyl group.
Example preferable substituents for the hydrocarbon group which may be
substituted for include (i) halogen, (ii) cycloalkyl group, (iii) aryl
group, (iv) amino group which may have an alkyl, alkenyl, cycloalkyl or
aryl group as a substituent, (v) hydroxyl group, (vi) optionally
halogenated alkoxy groups, (vii) acyl group, (viii) acyloxy group, (ix)
cyano group, (x) optionally protected carboxyl group and (xi) carbamoyl
group, with greater preference given to (a) C.sub.3-6 cycloalkyl group,
(b) C.sub.6-10 aryl group, (c) amino group which may be substituted by
C.sub.1-4 alkyl group, and (d) carboxyl group which may be substituted by
C.sub.1-4 alkyl group.
The definition of substituents as described in (i) to (x) and (a) to (d) is
the same meaning as defined in the above hydrocarbon group.
Examples of preferable groups for R.sup.1a, R.sup.1b and R in --OR include
a C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl, tert-butyl) or C.sub.3-6 cycloalkyl group (e.g. cyclopropyl)
which may be substituted by a (i) C.sub.6-10 aryl (e.g. phenyl), (ii)
amino which may be substituted by one or two C.sub.1-4 alkyl groups (e.g.
amino, methylamino, dimethylamino), (iii) hydroxyl, (iv) optionally
protected carboxyl (e.g. C.sub.1-6 alkoxy-carbonyl such as
methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl) or (v) C.sub.3-6
cycloalkyl (e.g. cyclopropyl), preferably, methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl,
benzyl, 2,2-dimethylaminoethyl, 2,2-diethylaminoethyl, 2-hydroxyethyl,
carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl and
t-butoxycarbonylmethyl. Hydrogen is also preferable for R.sup.1b.
Preferable groups for R.sup.2, R.sup.2a, R.sup.3a and R.sup.4a include
hydrogen atom and C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl,
isopropyl, etc.), with greater preference given to hydrogen atoms, methyl,
ethyl, propyl and isopropyl groups.
With respect to the above formulas, .alpha. represents 0, 1 or 2, with
preference given to 1.
In the above formulas, ........ represents a single or double bond; Z'
represents
##STR56##
(the symbols have the same definitions as above) or a nitrogen atom,
provided that ........ is a single bond, or a carbon atom, provided that
........ is a double bond.
In the above formulas, either X' or Y' represents --NR.sup.1a -- (the
symbols have the same definitions as above), --O-- or --S--, the other
representing --CO--, --CS-- or --C(R.sup.2)R.sup.2a -- (the symbols have
the same definitions as above), or either X' or Y' represents --N.dbd.,
the other representing .dbd.CR.sup.3a -- (the symbols have the same
definitions as above). --X'--Y'-- is preferably exemplified by --NR.sup.1a
-- CO--, --NR.sup.1a --CH.sub.2 --, --CO--NR.sup.1a --, --O--CO--,
--CO--O-- and --N.dbd.CR.sup.3a -- (the symbols have the same definitions
as above), more preferably --N(CH.sub.3)--CO--, --N(C.sub.2 H.sub.5)--
CO--, --N(CH.sub.3)--CH.sub.2 --, --N(C.sub.2 H.sub.5)--CH.sub.2 --,
--CO--N(CH.sub.3)--, --CO--N(C.sub.2 H.sub.5)--, --O--CO--, --CO--O--,
--N.dbd.CH--, --N.dbd.C(CH.sub.3)--, --N.dbd.C(OCH.sub.3)-- and
--N.dbd.C(OC.sub.2 H.sub.5)--.
In the above formulas, either X" or Y" represents --NR.sup.1b -- (the
symbols have the same definitions as above), --O-- or --S--, the other
representing --CO--, --CS-- or --C(R.sup.2)R.sup.2a -- (the symbols have
the same definitions as above), or either X" or Y" represents --N.dbd.,
the other representing .dbd.CR.sup.3a -- (the symbols have the same
definitions as above). --X"--Y"-- is preferably exemplified by --NR.sup.1b
-- CO--, --NR.sup.1b --CH.sub.2 --, --CO--NR.sup.1b --, --O--CO--,
--CO--O-- and --N.dbd.CR.sup.3a -- (the symbols have the same definitions
as above), more preferably --NHCO--, --N(CH.sub.3)--CO--, --N(C.sub.2
H.sub.5)--CO--, --N(CH.sub.3)--CH.sub.2 --, --N(C.sub.2 H.sub.5)--CH.sub.2
--, --CONH--, --CO--N(CH.sub.3)--, --CO-- N(C.sub.2 H.sub.5)--, --O--CO--,
--CO--O--, --N.dbd.CH--, --N.dbd.C(CH.sub.3)--, --N.dbd.C(OCH.sub.3)-- and
--N.dbd.C(OC.sub.2 H.sub.5)--.
With respect to the above formulas, two isomers exist with different
relative configurations of positions 3 and 4 on the condensed ring,
provided that ........ is a single bond and Z' is
##STR57##
(R.sup.4a has the same definitions as above), each of which isomers
involves two isomers with different absolute configurations. Provided that
........ is a single bond and Z' is a nitrogen atom, there are two isomers
with different absolute configurations of position 3. The present
invention includes these isomers and mixtures thereof. In this context,
the position 3 of the condensed ring indicates the position of the carbon
atom to which
##STR58##
is bound, the position 4 indicating the position of Z'. Preferable
examples of (I) and (I') include also compounds of the formula:
##STR59##
wherein rings A" and B" are an optionally substituted benzene ring;
R.sup.1c represents a hydrogen atom, a hydroxyl group, an optionally
substituted hydrocarbon group, an optionally substituted alkoxy group or
an optionally substituted amino group; Q represents an oxygen atom or a
sulfur atom;
D.sup.1 represents a C.sub.1-3 alkylene group which may be substituted by
an oxo or thioxo group;
provided that D.sup.1 is an unsubstituted C.sub.1-3 alkylene group, it may
cooperate with R.sup.1C to form a 5- to 7-membered ring which may be
substituted by an oxo or thioxo group; E.sup.2 represents --NR.sup.5a --
(R.sup.5a represents a hydrogen atom or an optionally substituted
hydrocarbon group), --O-- or --S--;
R.sup.5 and R.sup.1c, taken together, may form a 5- to 7-membered ring
which may be substituted by an oxo or thioxo group;
G.sup.3 represents a bond or a C.sub.1-3 alkylene group;
Ar' represents an optionally substituted aryl group or an optionally
substituted heterocyclic group; provided that, when --D.sup.1 --E.sup.2 --
is --(CH.sub.2).sub..beta. --CONH-- (.beta.is 0, 1 or 2), G.sup.3
represents a C.sub.1-3 alkylene group, or a salt thereof.
And, the compound (X) can be produced by a process which comprises reacting
a compound of the formula:
##STR60##
wherein L represents a leaving group; D.sup.1 and R.sup.1c do not bind
together to form a 5- to 7-membered ring; the other symbols are the same
meaning as defined hereinabove or salt thereof with a compound of the
formula:
H--E.sup.2 --G.sup.3 --Ar' (XII)
wherein all symbols are the same meanings as defined hereinabove or a salt
thereof.
Further the compound (X) can be produced by a process which comprises
reacting a compound of the formula:
##STR61##
wherein L' represents a leaving group; the other symbols are the same
meaning as defined hereinabove or salt thereof, with a compound of the
formula:
L'--G.sup.3 --Ar' (XIV)
wherein all symboles are the same meaning as defined hereinabove or a salt
thereof.
Preferable examples of the above symbols include the following:
(1) rings A" and B" are a benzene ring which may be substituted by one to
four substituents selected from the group consisting of halogen (e.g.
fluorine, chlorine, bromine), optionally halogenated C.sub.1-4 alkyl group
(e.g. methyl, trifluoromethyl, ethyl, propyl, isopropyl), hydroxyl group,
optionally halogenated C.sub.1-4 alkoxy group (e.g. methoxy,
trifluoromethoxy, ethoxy, propoxy, butoxy), optionally halogenated
C.sub.1-4 alkylthio group (e.g. mercapto, methylthio, trifluoromethylthio,
ethylthio), amino group, mono- or di-C.sub.1-4 alkylamino group (e.g.
methylamino, ethylamino, dimethylamino), carboxyl group and C.sub.1-4
alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl),
(2) ring A" is represented by the general formula:
##STR62##
wherein A.sup.4a, A.sup.5a and A.sup.6a, whether identical or not,
independently represent a halogen atom (e.g. fluorine, chlorine, bromine),
an optionally halogenated C.sub.1-4 alkyl group (e.g. methyl,
trifluoromethyl, ethyl, propyl, isopropyl) or an optionally halogenated
C.sub.1-4 alkoxy group (e.g. methoxy, trifluoromethoxy, ethoxy, propoxy,
butoxy),
(3) ring B" is represented by the general formula:
##STR63##
wherein B.sup.4b, B.sup.5b and B.sup.6b, whether identical or not,
independently represent a halogen atom, an optionally halogenated
C.sub.1-4 alkyl group (e.g. methyl, trifluoromethyl, ethyl, propyl,
isopropyl) or an optionally halogenated C.sub.1-4 alkoxy group (e.g.
methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy),
(4) R.sup.1c is a hydrogen atom or a C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl) which may be substituted by one or two substituents
selected from the group consisting of hydroxyl group, C.sub.1-4 alkoxy
group (e.g. methoxy, ethoxy), amino group, mono- or di-C.sub.1-4
alkylamino group (e.g. methylamino, ethylamino, dimethylamino,
diethylamino), C.sub.1-4 alkoxy-carbonyl group (e.g. methoxycarbonyl,
ethoxycarbonyl), carboxyl group, carbamoyl group and phenyl group,
(5) R.sup.1c is a hydrogen atom or a C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl),
(6) R.sup.5a is a hydrogen atom or a C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl) which may be substituted for by one or two substituents
selected from the group consisting of hydroxyl group, C.sub.1-4 alkoxy
group (e.g. methoxy, ethoxy, propoxy), amino group, mono- or di-C.sub.1-4
alkylamino group (e.g. methylamino, ethylamino, dimethylamino,
diethylamino), C.sub.1-4 alkoxy-carbonyl group (e.g. methoxycarbonyl,
ethoxycarbonyl), carboxyl group, carbamoyl group and phenyl group,
(7) R.sup.5a is a hydrogen atom or a C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl),
(8) the optionally substituted aryl group represented by Ar', is a
C.sub.6-10 group (e.g. phenyl, naphthyl) which may have one to three
substituents selected from the group consisting of an optionally
halogenated C.sub.1-4 alkyl group (e.g. methyl, trifluoromethyl, ethyl,
propyl, isopropyl), halogen atom (e.g. fluorine, chlorine, bromine), nitro
group, hydroxyl group, optionally halogenated C.sub.1-4 alkoxy group (e.g.
methoxy, trifluoromethoxy, ethoxy, butoxy), amino group, mono- or
di-C.sub.1-4 alkylamino group (e.g. methylamino, ethylamino,
dimethylamino, diethylamino), C.sub.1-4 alkoxy-carbonyl group (e.g.
methoxycarbonyl, ethoxycarbonyl), carboxyl group and carbamoyl group,
(9) the optionally substituted aryl group represented by Ar', is a phenyl
group which may have one to three substituents selected from the group
consisting of an optionally halogenated C.sub.1-4 alkyl group (e.g.
methyl, trifluoromethyl, ethyl, propyl, isopropyl), halogen atom (e.g.
fluorine, chlorine, bromine) and C.sub.1-4 alkoxy group (e.g. methoxy,
ethoxy, propoxy),
(10) the optionally substituted heterocyclic group represented by Ar', is
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,
pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl or
thiophenyl which may have one to three substituents selected from the
group consisting of halogen atom (e.g. fluorine, chlorine, bromine),
optionally halogenated, C.sub.1-4 alkyl group (e.g. methyl,
trifluoromethyl, ethyl, propyl, isopropyl), C.sub.3-6 cycloalkyl group
(e.g. cyclopropyl), hydroxyl group, C.sub.1-4 alkoxy group (e.g. methoxy,
ethoxy, propoxy), C.sub.1-4 alkylthio group (e.g. methylthio, ethylthio,
propylthio), amino group, mono- or di-C.sub.1-4 alkylamino group (e.g.
methylamino, ethylamino, dimethylamino, diethylamino), C.sub.1-4
alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl) and carboxyl
group,
(11) the heterocyclic group represented by Ar', is furyl, thienyl or
pyridyl which may have one to three substituents selected from the group
consisting of halogen atom (e.g. fluorine, chlorine, bromine), C.sub.1-4
alkyl group (e.g. methyl, ethyl, propyl) and C.sub.1-4 alkoxy group (e.g.
methoxy, ethoxy, propoxy),
(12) Q is an oxygen atom.
(13) D.sup.1 is --CO--, --CS--, --CH.sub.2 --, --CH.sub.2 CH.sub.2 --,
--CH.sub.2 CO-- or --CH.sub.2 CH.sub.2 CO--,
(14) D.sup.1 is --CO-- or --CH.sub.2 CO--,
(15) D.sup.1 is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --,
(16) D.sup.1 is --CO-- or --CH.sub.2 --,
(17) E.sup.2 is --NR.sup.5c -- (R.sup.5c is a hydrogen atom or a C.sub.1-4
alkyl group (e.g. methyl, ethyl, propyl)),
(18) E.sup.2 is --O--,
(19) G.sup.3 is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --,
(20) ring A" is a benzene ring which may be substituted by two C.sub.1-4
alkyl group (e.g. methyl, ethyl, propyl); ring B is a benzene ring which
may be substituted by a C.sub.1-4 alkyl group (e.g. methyl, ethyl,
propyl); R.sup.1c is a C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl),
R.sup.5a is a hydrogen atom or a C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl), D.sup.1 is --CO--; E.sup.2 is --NR.sup.5c -- (R.sup.5c
represents a hydrogen atom or a C.sub.1-4 alkyl group (e.g. methyl, ethyl,
propyl)), G.sup.3 is --CH.sub.2 --; Ar' is a phenyl group substituted by
one to three optionally halogenated C.sub.1-4 alkyl groups (e.g. methyl,
trifluoromethyl, ethyl),
(21)
N--(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-2-methyl-4-(2-methylphenyl)-
1-oxo-3-isoquinolinecarboxamide,
N-(3,5-bistrifluoromethyl)benzyl-1,2-dihydro-N,2-dimethyl-4-(2-methylpheny
l)-1-oxo-3-isoquinolinecarboxamide or
N-›3,5-bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2,6,7-tetra
methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide,
The terms of ring A" and B" are the same meaning as defined above in the
ring A and B of (I) and (I').
Preferable substituents on ring A" and B" include halogen (e.g. fluoro,
chloro, bromo, etc.), optionally halogenated C.sub.1-4 alkyl (e.g. methyl,
chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluropropyl,
isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl, tert-butyl, etc.), optionally halogenated C.sub.1-4 alkoxy
(e.g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy,
isobutoxy, sec-butoxy, etc.), optionally substituted C.sub.1-4 alkylthio
(e.g. methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
propylthio, isopropylthio, buthylthio, 4,4,4-trifluorobuthylthio, etc.),
hydroxyl, amino, mono-or di-C.sub.1-4 alkylamino (e.g. methylamino,
ethylamino, propylamino, dimethylamino, diethylamino, etc.), carboxyl and
C.sub.1-4 alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, etc.).
More preferable substituents on ring A" and B" include halogen (e.g.
fluoro, chloro, bromo, etc.), optionally halogenated C.sub.1-4 alkyl (e.g.
methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,
ethyl, 2-bromoethyl, 2,2,2,-trifluoroethyl, propyl, 3,3,3-trifluoropropy
isopropyl, 2-trifluoromethylethyl, buthyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl, tert-butyl, etc.), optionally halogenated C.sub.1-4 alkoxy
(e.g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy,
isobutoxy, sec-butoxy, etc.), hydroxyl, amino and mono- or di- C.sub.1-4
alkylamino (e.g. methylamino, ethylamino, propylamino, dimethylamino,
diethylamino, etc.).
Specifically more preferable substituents on ring A" and B" include halogen
(e.g. fluoro, chloro, bromo, etc.), optionally halogenated C.sub.1-4 alkyl
(e.g. methyl, chloromethyl, difluoromethyl, trichloromethyl,
trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,
3,3,3-trifluoropropy isopropyl, 2-trifluoromethylethyl, buthyl,
4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, etc.), optionally
halogenated C.sub.1-4 alkoxy (e.g. methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,
butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, etc.).
The substituent(s) for rings A" and B" may be located at any position on
the ring. When two or more substituents are present, they may be identical
or not, the number of substituents being 1 to 4, preferably 1 to 3, more
preferably 1 or 2. Also, the adjacent carbons on ring A" or B" may bind
with a group represented by --(CH.sub.2)l-- (l represents an integer of
from 3 to 5) to form a 5- to 7-membered ring.
Referring to ring A", concrete examples of the moiety
##STR64##
include groups of the formula:
##STR65##
where A.sup.4a, A.sup.5a and A.sup.6a are the same or different and each
means a halogen atom such as chloro, fluoro, etc., an optionally
halogenated C.sub.1-4 alkyl group such as methyl, ethyl, isopropyl
trifluoromethyl, etc., or an optionally halogenated C.sub.1-4 alkoxy group
such as methoxy, trifluoromethoxy, ethoxy, etc.
In A.sup.4a, A.sup.5a and A.sup.6a, preferably a C.sub.1-4 alkyl group
(e.g. methyl, ethyl, etc.).
Referring to ring B", concrete examples of the moiety
##STR66##
include groups of the formula:
##STR67##
where B.sup.4b, B.sup.5b, B.sup.6b, B.sup.7b, B.sup.8b and B.sup.9b are
the same or different and each means a halogen atom such as chloro,
fluoro, etc., an optionally halogenated C.sub.1-4 alkyl group such as
methyl, trifluoromethyl, ethyl, etc., or an optionally halogenated
C.sub.1-4 alkoxy group such as methoxy trifluoromethoxy, ethoxy, etc.
Preferred examples of the ring B" are groups of the formula:
##STR68##
wherein B.sup.4b, B.sup.5b and B.sup.6b is the same meaning hereinbefore.
In B.sup.4b, B.sup.5b and B.sup.6b, preferably a C.sub.1-4 alkyl group
(e.g. methyl, ethyl, etc.) and a C.sub.1-4 alkoxy group (e.g. methoxy,
ethoxy, etc.).
With respect to the above formula, R.sup.1c represents a hydrogen atom,
hydroxyl group, optionally substituted hydrocarbon group, optionally
substituted alkoxy group or optionally substituted amino group. The
"hydrocarbon group" of "optionally substituted hydrocarbon group"
represented by R.sup.1c is used, for example, C.sub.1-6 alkyl group,
C.sub.3-6 cycloalkyl group or C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl group
and so on. The C.sub.1-6 alkyl group includes, for example, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
neopentyl, hexyl, etc., preferably a C.sub.1-4 alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. The
C.sub.3-6 cycloalkyl group includes, for example, cyclopropyl, cyclopentyl
or cyclohexyl, etc. The C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl group
includes, for example, cyclopropylmethyl, cyclopropylethyl, etc.
The preferable substituent of the hydrocarbon group hereinabove is commonly
used a C.sub.1-4 alkyl group such as methyl, ethyl, propyl, isopropyl,
butyl and so on.
The substituent of the hydrocarbon group is used one to five, preferably
one to three, more preferable one or two substituent(s) selected from the
group consisting of halogen atom (e.g. fluoro, chloro, bromo, etc.),
nitro, cyano, hydroxyl, C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy,
propoxy, butoxy, isopropoxy, etc.), C.sub.1-4 alkylthio group (e.g.
methylthio, ethylthio, propylthio, etc.), amino, mono- or di- C.sub.1-4
alkylamino group (e.g. methylamino, ethylamino, propylamino,
dimethylamino, diethylamino, etc.), cyclic amino group (e.g., 5- to
9-membered cyclic amino which may contain 1 to 3 hetero-atoms such as
oxygen and sulfur in addition to nitrogen as ring-constituent members,
such as pyrrolidino, piperidino, morpholino, etc.), C.sub.1-4
alkyl-carbonylamino group (e.g. acetylamino, propionylamino, butyrylamino,
etc.), C.sub.1-4 alkylsulfonylamino group (e.g. methylsulfonylamino,
ethylsulfonylamino, etc.), C.sub.1-4 alkoxy-carbonyl group (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl,
C.sub.1-6 alkyl-carbonyl group (e.g. methylcarbonyl, ethylcarbonyl,
propylcarbonyl, etc.), carbamoyl, ethylcarbamoyl, etc.), mono- or
di-C.sub.1-4 alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.),
C.sub.1-6 alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl,
propylsulfonyl, etc.), and pheny group which may be substituted by
C.sub.1-3 alkoxy group (e.g. methoxyphenyl, ethoxyphenyl, etc.).
As the halogen atoms, among the above-mentioned substituents, fluoro,
chloro, bromo and iodo may be reckoned and chloro or fluoro is preferred.
Preferable examples of substituent of hydrocarbon group include hydroxyl
group, C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.), amino
group, mono- or di- C.sub.1-4 alkylamino group (e.g. methylamino,
ethylamino, dimethylamino, diethylamino, etc.), C.sub.1-4 alkoxy-carbonyl
group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.),
carboxyl group, carbamoyl group, phenyl group, more preferably carboxyl
group and carbamoyl group.
Preferable examples of R.sup.1c include a hydrogen atom and a C.sub.1-4
alkyl group (e.g. methyl, ethyl, n-propyl, n-butyl, etc.), more preferably
a C.sub.1-4 alkyl group (e.g. methyl, ethyl, n-propyl, etc.),
The "alkoxy group" of the "optionally substituted alkoxy group" represented
by R.sup.1c is, for example, C.sub.1-4 alkoxy group (e.g. methoxy, ethoxy,
propoxy, isopropoxy, butoxy, t-butoxy, etc.) and so on. The substituent of
the "alkoxy group" is the same meaning as defined in the substituent of
"hydrocarbon group".
The substituent of the "optionally substituted amino group" represented by
R.sup.1c includes (i) C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl,
isopropyl, etc.), (ii) C.sub.1-4 alkyl-carbonyl group (e.g. acetyl,
propyonyl, butyril, etc.), (iii) C.sub.1-4 alkoxy-carbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), (iv) halogen atom
(e.g. fluoro, chloro, etc.) and (v) phenyl group which may be substituted
by a C.sub.1-4 alkyl (e.g. methyl, ethyl, etc.), a C.sub.1-4 alkoxy group
(e.g. methoxy, ethoxy, etc.) or a halogen atom (e.g. fluoro, chloro, etc.)
such as phenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl,
4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3-methoxyphenyl,
2-methoxyphenyl, etc. The optionally substituted amino group may be
substituted by one or two substituent(s).
With respect to the above formula, Q represents an oxygen atom and a sulfur
atom, preferably an oxygen atom.
With respect to the above formula, D.sup.1 represents a C.sub.1-3 alkylene
group which may be substituted by an oxo or thioxo group.
The C.sub.1-3 alkylene group includes, for example, --CH.sub.2 --,
--CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 -- and
--CH(CH.sub.3)--CH.sub.2 -- and so on.
Preferable examples of D.sup.1 include --CO--, --CS--, --CH.sub.2 --,
--CH.sub.2 CH.sub.2 --, --CH.sub.2 CO--, --CH.sub.2 CS--, --CH.sub.2
CH.sub.2 CO-- and --CH.sub.2 CH.sub.2 CS--, more preferably --CO--,
--CH.sub.2 --, --CH.sub.2 CH.sub.2 -- and --CH.sub.2 CO--, specially
--CO-- and --CH.sub.2 -- are more preferable.
Provided that D.sup.1 is an unsubstituted C.sub.1-3 alkylene group, its
carbon atoms may cooperate with R.sup.1c to form a 5- to 7-membered ring
which may be substituted by an oxo or thioxo group. Specifically, the
compound (X) is represented by the formula:
##STR69##
wherein ring K' is a 5- to 7-membered ring which may be substituted by an
oxo or thioxo group; h represents an integer from 3 to 5; the other
symbols have the some definitions as above, or a salt thereof, preferably
represented by the formula:
##STR70##
wherein the symbols have the same definitions as above or below.
With respect to the above formulas, E.sup.2 represents --NR.sup.5a --
(R.sup.5a represents a hydrogen atom or an optionally substituted
hydrocarbon group), --O-- or --S--. The hydrocarbon group represented by
R.sup.5a is preferably a C.sub.1-6 alkyl group, a C.sub.3-6 cycloalkyl
group, a C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl group or the like, more
preferably a C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl). The
C.sub.1-46 alkyl group is exemplified by methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl, with
preference given to C.sub.1-4 alkyl groups such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The C.sub.3-6
cycloalkyl group is exemplified by cyclopropyl, cyclopentyl and
cyclohexyl. The C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl group is exemplified
by cyclopropylmethyl and cyclopropylethyl. R.sup.5a is preferably a
hydrogen atom or a C.sub.1-4 alkyl group (e.g., methyl, ethyl, propyl,
isopropyl, butyl), with greater preference given to C.sub.1-4 alkyl groups
(e.g., methyl, ethyl, propyl, isopropyl). The substituent the alkyl group
may have is exemplified by the same groups as the "substituents" for the
"optionally halogenated hydrocarbon group" represented by R.sup.1c.
Preferable substituents for the hydrocarbon group represented by R.sup.5a
are the same as specified for substituents for the hydrocarbon group
represented by R.sup.1c ; C.sub.1-3 alkoxy group (e.g., methoxy, ethoxy),
mono- or di-C.sub.1-2 alkylamino group (e.g., dimetylamino), carbamoyl
group, carboxyl group etc. are used commonly. The number of substituents
is preferably 1 or 2. Preferable examples or E.sup.2 are --NH-- or --O--.
Also, R.sup.5a and R.sup.1c may bind together to form a 5- to 7-membered
ring which may be substituted by an oxo or thioxo group. Specifically, the
compound (X) is represented by the general formula:
##STR71##
wherein ring K" is a 5- to 7-membered ring which may be substituted by an
oxo or thioxo group; i represents an integer from 1 to 3, the total carbon
number of D.sup.1 and --(CH.sub.2).sub.i -- being 3 to 5; the other
symbols have the same definitions as above or below. Preferably, it is
represented by the formula:
##STR72##
wherein D.sup.a and M independently represent --CH.sub.2 -- or --CO--; the
other symbols have the same definitions as above or below.
In the above formulas, Ar' represents an aryl group which may have an
optionally substituted substituent or an optionally substituted
heterocyclic group. The optionally substituted aryl group is the same
meaning as defined in Ar.
Preferable examples of substituent of the aryl group represented by Ar'
include optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,
3,3,3-trifluoropropyl), halogen atom (e.g., fluorine, chlorine, bromine),
nitro group, hydroxyl group, optionally halogenated C.sub.1-4 alkoxy group
(e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy), amino group, mono- or di-C.sub.1-4 alkylamino
group (e.g., methylamino, ethylamino, dimethylamino, diethylamino),
C.sub.1-4 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl),
carboxyl group and carbamoyl group, more preferably, optionally
halogenated C.sub.1-4 alkyl group (e.g., methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl),
halogen atom (e.g., fluorine, chlorine, bromine) and C.sub.1-4 alkoxy
group (e.g., methoxy, ethoxy, propoxy).
The heterocyclic group represented by Ar', is exemplified by 5- to
9-membered, preferably 5- or 6-membered aromatic heterocyclic groups which
may have one to four, preferably one or two hetero atoms such as nitrogen,
oxygen and sulfur atoms in addition to carbon atoms.
Such aromatic heterocyclic group is the same meaning as defined in Ar.
Preferable example of the heterocyclic group represented by Ar' include 5-
or 6-membered heterocyclic groups such as furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,
quinolyl, isoquinolyl, thiazolyl, thiadiazolyl and thiophenyl, with
greater preference given to furyl, thienyl, pyridyl etc.
The substituent in the "optionally substituted heterocyclic group,"
represented by Ar', is the same meaning as defined in Ar.
Preferable examples of substituent of the heterocyclic ring represented by
Ar' include halogen atom (e.g., fluorine, chlorine, bromine), optionally
halogenated C.sub.1-4 alkyl group (e.g., methyl, chloromethyl,
difluoromethyl, trifluoromethyl, ethyl), C.sub.3-6 cycloalkyl group (e.g.,
cyclopropyl, cyclobutyl), hydroxyl groups, optionally halogenated
C.sub.1-4 alkoxy group (e.g., methoxy, difluoromethoxy, trifluoromethoxy,
ethoxy), optionally halogenated C.sub.1-4 alkylthio group which may be
halogenated (e.g., methylthio, ethylthio), amino group, mono- or
di-C.sub.1-4 alkylamino group (e.g., methylamino, ethylamino,
dimethylamino, diethylamino), C.sub.1-4 alkoxy-carbonyl groups (e.g.,
methoxycarbonyl, ethoxycarbonyl) and carboxyl group, with greater
preference given to halogen atom (e.g., fluorine, chlorine), C.sub.1-4
alkyl group (e.g., methyl, ethyl), C.sub.3-6 cycloalkyl group (e.g.,
cyclopropyl, cyclobutyl), hydroxyl group, C.sub.1-4 alkoxy group (e.g.,
methoxy, ethoxy) and carboxyl groups etc.
Ar' is preferably a phenyl group which may have one to three substituents
selected from the group consisting of halogen atom (e.g., fluorine,
chlorine), optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, propyl,
isopropyl) and optionally halogenated C.sub.1-4 alkoxy group (e.g.,
methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,
propoxy, isopropoxy). Also preferred are 5- or 6-membered heterocyclic
group (e.g., furyl, pyridyl, thienyl, thiazolyl, thiadiazolyl) which have
one to three hetero atom (e.g., nitrogen atoms, oxygen atoms, sulfur
atoms) in addition to carbon atoms and which may be substituted by an
optionally halogenated C.sub.1-4 alkyl group (e.g., methyl,
trifluoromethyl, ethyl), a C.sub.1-4 alkoxy group (e.g., methoxy, ethoxy,
propoxy) or a C.sub.3-6 cycloalkyl group (e.g., cyclopropyl).
G.sup.3 represents a bond or a C.sub.1-3 alkylene group. The C.sub.1-3
alkylene group include --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2
CH.sub.2 CH.sub.2 -- and --CH(CH.sub.3)CH.sub.2 --. G.sup.3 is preferably
--CH.sub.2 -- or --CH.sub.2 CH.sub.2 --, --CH.sub.2 -- being commonly
used.
In the above formula, L represents a leaving group. This group is
exemplified by hydroxyl group, halogen atom (e.g., chlorine, bromine,
iodine), substituted sulfonyloxy group (e.g., methanesulfonyloxy and
p-toluenesulfonyloxy groups), acyloxy group (e.g., acetoxy and benzoyloxy
groups), and oxy group substituted by a heterocyclic group or an aryl
group (e.g., succinimide, benzotriazole, quinoline or 4-nitrophenyl
group).
In the above formula, L' and L" represents a leaving group. This leaving
group is exemplified by halogen atom and substituted sulfonyloxy group
among the leaving groups exemplified for L above.
When compound (I) and (I') of the present invention has a basic group such
as an amino group or a substituted amino group, it may form a
physiologically acceptable acid addition salt. Such salts include those
with inorganic acids (e.g., hydrochloric acid, phosphoric acid,
hydrobromic acid, sulfuric acid) and those with organic acids (e.g.,
acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,
succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,
benzoic acid, methanesulfonic acid, benzenesulfonic acid). When compound
(I) and (I') of the present invention has an acidic group such as --COOH,
it may form a salt with an inorganic base (e.g., alkali metals or alkaline
earth metals such as sodium, potassium and magnesium, ammonia) or an
organic base (e.g., tri-C.sub.1-3 alkylamine such as triethylamine).
Production methods for compound (I) and (I') or a salt thereof of the
present invention are described below.
Compound (I) and (I') or a salt thereof of the present invention can, for
example, be produced by the following methods 1 and 2. Specifically,
compound (I) and (I') or a salt thereof is produced by 1 reacting a
heterocyclic compound or a salt thereof having a leaving group L,
represented by general formula (II) and a compound or a salt thereof
represented by formula (III), or by 2 reacting a heterocyclic compound or
a salt thereof represented by general formula (IV) and a compound or a
salt thereof represented by formula (V).
Methods 1 and 2 are hereinafter described in detail.
Method 1
This method generally affords two options: i) acylation, conducted when the
L-linked methylene group in D is substituted by an oxo or thioxo group,
and ii) alkylation, conducted when the L-linked methylene group in D is
unsubstituted.
i) Acylation: When the leaving group L of compound (II) is a hydroxyl
group, it is preferable to use an appropriate condensing agent or to
convert the leaving hydroxyl group to another leaving group as appropriate
(e.g., an acyloxy group as described above, or an oxy group substituted by
a heterocyclic group or aryl group) and then react it with compound (III)
or a salt thereof. Such condensing agents include dicyclohexylcarbodiimide
(DCC), diethyl cyanophosphate (DEPC) and diphenylphosphorylazide (DPPA).
When these condensing agents are used, the reaction is preferably carried
out in a solvent (e.g., ethers, esters, hydrocarbons, amides, sulfoxides)
such as tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene,
toluene, N,N-dimethylformamide and dimethylsulfoxide. This reaction may be
accelerated in the presence of a base, and is carried out at about
-10.degree. to 100.degree. C., preferably about 0.degree. to 60.degree. C.
Reaction time is normally 5 minutes to 96 hours, preferably 0.5 to 72
hours. The mount of compound (III) or a salt thereof or condensing agent
used is 1 to 5 mol equivalents, preferably 1 to 3 mol equivalents per mol
of compound (II) or a salt thereof. Examples of bases which can be used
include alkylamines such as triethylamine and cyclic amines such as
N-methylmorpholine and pyridine, their amount being 1 to 5 mol
equivalents, preferably 1 to 3 mol equivalents per mol of compound (II) or
a salt thereof.
Compound (II) as a reactive derivative is preferably an acid halide (e.g.,
chloride, bromide), acid anhydride, mixed acid anhydride (e.g., anhydride
with methylcarbonic acid, anhydride with ethylcarbonic acid, anhydride
with isobutylcarbonic acid), active ester (e.g., ester with
hydroxysuccinimide, ester with 1-hydroxybenzotriazole, ester with
N-hydroxy-5-norbornane-2,3-dicarboxymide, ester with p-nitrophenol, ester
with 8-oxyquinoline), with preference given to acid halides. The reaction
of compound (III) or a salt thereof and compound (II) is normally carried
out in a solvent (e.g., halogenated hydrocarbons ethers, esters,
hydrocarbons, amides such as chloroform, dichloromethane, ethyl ether,
tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene,
toluene, pyridine, and N,N-dimethylformamide). This reaction may be
accelerated in the presence of a base. Reaction temperature is normally
about -10.degree. to 120.degree. C., preferably about 0.degree. to
100.degree. C. Reaction time is normally 5 minutes to 48 hours, preferably
0.5 to 24 hours. The mounts of compound (III) used is 1 to 5 mol
equivalents, preferably 1 to 3 mol equivalents per mol of compound (II) or
a salt thereof. Examples of bases which can be used include alkylamines
such as triethylamine, cyclic mines such as N-methyl-morpholine and
pyridine, aromatic amines such as N,N-dimethylaniline and
N,N-diethylaniline, alkali metal carbonates such as sodium carbonate and
potassium carbonate and alkali metal hydrogen carbonates such as sodium
hydrogen carbonate and potassium hydrogen carbonate, their amount being 1
to 5 mol equivalents, preferably 1 to 3 mol equivalents per mol of
compound (III) or a salt thereof. Also, when a water-immiscible solvent is
used for the reaction, the reaction system may consist of two phases
including water.
ii) Alkylation: In the reaction with compound (III), the leaving group L of
compound (II) is preferably one of the above-mentioned halogen atoms or
substituted sulfonyloxy groups.
Although compound (III) may be used as such in a free form, it may be
converted to a salt such as with an alkali metal such as lithium, sodium
or potassium before being used in the reaction. The amount of compound
(III) or a salt thereof reacted is 1 to 10 mol equivalents, preferably 1
to 5 mol equivalents per mol of compound (II). This reaction is normally
carried out in a solvent. Preferable solvents include halogenated
hydrocarbons such as dichloromethane and chloroform, nitriles such as
acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, and
dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide. Addition
of a base promotes the reaction. Bases preferred for this purpose include
sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate,
potassium carbonate, sodium hydride, potassium hydride, sodium amide,
sodium methoxide, triethylamine, diisopropylethylamine and pyridine. Also,
in this reaction, compound (III) may be converted to one of the
above-mentioned alkali metal salts, alkaline earth metal salts etc. and
then reacted with compound (II), in place of using a base. When E of
compound (II) is --NR.sup.5 --, compound (III) itself may be used as a
base, in place of using one of the above bases. Varying depending on types
of compounds (II) and (III) and solvent and other reaction conditions, the
mount of base used is normally 1 to 10 mol equivalents, preferably 1 to 5
mol equivalents per mol of compound (III). Reaction temperature is about
-50.degree. to 200.degree. C., preferably -20.degree. to 150.degree. C.
Varying depending on type of compound (III) or a salt thereof, reaction
temperature and other factors, reaction time is 1 to 72 hours, preferably
1 to 24 hours.
Method 2
This method is carried out in the same manner as the alkylation described
in term ii), method 1. Specifically, the same procedures as those of the
method described in term ii) is followed, using compound (V) in place of
compound (II) and using compound (IV) or a salt thereof in place of
compound (III) or a salt thereof.
Of the compounds represented by formula (I), a compound or a salt thereof
represented by the general formula (I.sup.a):
##STR73##
wherein either of X.sup.a and Y.sup.a is --NR.sup.1a -- (R.sup.1a had the
same definition as above) or --O--, the other representing --CO--; the
other symbols have the same definitions as above, can be produced by
subjecting to reduction a compound or a salt thereof represented by
formula (I.sup.b):
##STR74##
wherein the symbols have the same definitions as above.
This reaction, wherein an amide compound represented by general formula
(I.sup.b) is reduced to convert its double bond to a single bond, is
carried out by various methods. For example, it is preferable to use a
method wherein the starting material is reduced in the presence of a metal
catalyst for catalytic reduction. Examples of the catalysts for this
catalytic reduction method include platinum catalysts such as platinum
black, platinum oxide and platinum carbon, palladium catalysts such as
palladium black, palladium oxide, palladium barium sulfate and palladium
carbon, and nickel catalysts such as reduced nickel, oxidized nickel,
Raney nickel and Urushibara nickel. This reaction is normally carried out
in a solvent. An organic acid such as formic acid, acetic acid or
propionic acid is used as the solvent, or an alcohol such as methanol,
ethanol, propanol or isopropanol, an ether such as tetrahydrofuran or
dioxane, or an ester such as ethyl acetate, is used as the solvent in the
presence of the above organic acid or an inorganic acid such as phosphoric
acid, sulfuric acid or hydrochloric acid. Reaction temperature is normally
0.degree. to 200.degree. C., preferably 20.degree. to 110.degree. C.
Reaction time is normally 0.5 to 48 hours, preferably 1 to 16 hours.
Although the reaction is normally carried out under normal pressure, it
may be carried out under increased pressure (3 to 10 atm) as necessary.
Varying depending on catalyst type, the amount of catalyst used is
normally 0.1 to 10% (w/w), relative to compound (I.sup.b).
Of the compounds represented by formula (I), a compound represented by the
general formula (I.sup.c):
##STR75##
wherein the symbols have the same definitions as above or a salt thereof
can be produced by reacting a compound represented by general formula
(I.sup.d):
##STR76##
wherein the symbols have the same definitions as above, or a salt thereof
with an alkylating agent represented by the formula R.sup.1 -L (R.sup.1
has the same definition as above; L represents a leaving group) to produce
a compound represented by general formula (I.sup.e):
##STR77##
wherein the symbols have the same definitions as above or a salt thereof,
which is then subjecting to a reducing reaction.
This reaction, wherein a quinolineamide compound represented by general
formula (I.sup.d) is reacted with an alkylating agent represented by
R.sup.1 -L to a quaternary salt (I.sup.e), which is then reduced to
produce a compound represented by general formula (I.sup.c). Examples of
the alkylating agent R.sup.1 -L used to convert formula (I.sup.d) to
(I.sup.e) include alkane halides (e.g., chloride, bromide, iodide),
sulfates and sulfonates (e.g., methanesulfonate, p-toluenesulfonate,
benzenesulfonate), with preference given to alkyl halides. The amount of
alkylating agent used is 1 to 100 mol equivalents, preferably 1 to 30 mol
equivalents per mol of compound (I.sup.d). This reaction is normally
carried out in a solvent. Examples of the solvent include alcohols such as
methanol, ethanol, propanol and isopropanol, ethers such as
tetrahydrofuran and dioxane, esters such as ethyl acetate, and halogenated
hydrocarbons such as dichloromethane and 1,2-dichloroethane. The
alkylating agent itself may be used as the solvent. Reaction temperature
is normally 10.degree. to 200.degree. C., preferably 20.degree. to
110.degree. C. Reaction time is normally 0.5 to 24 hours, preferably 1 to
16 hours.
The thus-obtained quaternary salt (I.sup.e) is normally reduced to
(I.sup.c) in an inert solvent in the presence of a metal hydride. Examples
of metal hydrides which can be used for this purpose include sodium
borohydride, lithium borohydride, zinc borohydride, sodium
cyanoborohydride and lithium cyanoborohydride, with preference given to
sodium borohydride. Reaction solvents which can be used include lower
alcohols such as methanol and ethanol, ethers such as dioxane and
tetrahydrofuran and hydrocarbons such as benzene and toluene. These
solvents may be used singly or in combination. Reaction temperature is
normally about -100.degree. to 40.degree. C., preferably about -80.degree.
to 25.degree. C. Reaction time is normally 5 minutes to 10 hours,
preferably 10 minutes to 5 hours. The amount of reducing agent used is
normally 1 to 2 mol equivalents per mol of compound (II). Also, of the
compounds represented by formula (I) and (I'), a compound represented by
the general formula:
##STR78##
wherein D' represents a C.sub.1-3 alkylene group; the other symbols have
the same definitions as above or a salt thereof, can also be produced by a
reaction of a compound represented by the general formula:
##STR79##
wherein the symbols have the same definitions as above or a salt thereof,
and a compound represented by the general formula:
Ar--G'--CHO (XVI)
wherein G' represents a bond or a C.sub.1-2 alkylene group; the other
symbols have the same definitions as above, in the presence of a reducing
agent. This reaction is carried out by various methods; for example, the
reducing reaction described by R. F. Botch et al. in the Journal of
American Chemical Society, Vol. 93, pp. 2897-2904 (published 1971) or a
method based thereon is preferably used. Also, a compound of general
formula (I) and (I') wherein D is a C.sub.1-3 alkylene group and E is
--NH-- can be reacted with a carbonyl compound represented by the general
formula:
##STR80##
wherein R.sup.5 p and R.sup.5 q, whether identical or not, independently
represent hydrogen or an optionally substituted hydrocarbon group, in the
presence of a reducing agent, for example, the above-mentioned method of
Borch et al. or a method based thereon, to yield a compound or a salt
thereof represented by the general formula:
##STR81##
wherein R.sup.5d represents an optionally substituted hydrocarbon group;
the other symbols have the same definitions as above.
A compound of general formula (I-B), one of the desired compounds described
above, which has a tricyclic structure, can, for example, be produced by
the following methods a) and b).
Method a)
A compound represented by the general formula:
##STR82##
wherein j represents an integer from 0 to 2; the other symbols have the
same definitions as above or a salt thereof or a reactive derivative
thereof derivatized at the carboxyl group thereof (included in the desired
compound of the present invention and produced by the above Method 1 or 2)
is cyclized by intramolecular amidation to yield a compound represented by
the general formula:
##STR83##
wherein the symbols have the same definitions as above or a salt thereof.
Method b)
A compound represented by the general formula:
##STR84##
wherein D" represents --CH.sub.2 -- or --CO--; L" represents a leaving
group; k represents an integer from 1 to 3; the other symbols have the
same definitions as above (included in the desired compound of the present
invention and produced by the above method 1 or 2) or a salt thereof, is
cyclized by intramolecular alkylation to yield a compound or salt thereof
represented by the general formula:
##STR85##
wherein the symbols have the same definitions as above or a salt thereof.
The above Method a), based on amide bond forming reaction, is carried out
by various procedures. For example, the same procedures as described in
method 1-i) may be used. Method b), based on alkylation, is carried out by
the s-me procedures as described in method 1-ii) or method 2 may be used.
It is also possible to produce a compound of formula (I) wherein E is
--NR.sup.5d -- (the symbols have the same definitions as above) by
alkylating a compound of formula (I) and (I') wherein E is --NH-- with an
alkylating agent represented by the formula R.sup.5e -L" (R.sup.5e
represents an optionally substituted alkyl group; L" represents a leaving
group) by the same method as described in method 1-ii).
(iii) Of the compounds represented by the formula (I), a quinoline or an
isoquinoline compound represented by the general formula: wherein
--X.sup.b --Y.sup.b -- represents --N.dbd.CR.sup.3 -- or --CR.sup.3
.dbd.N-- (R.sup.3 represents the same meaning as defined above), E'
represents --NR.sup.5f --(R.sup.5f represents an optionally
##STR86##
substituted hydrocarbon group), --O-- or --S(O)n--(n is 0, 1 or 2) and the
other symbols are the same meaning as defined above, can be produced from
a quinolone or an isoquinolone compound represented by the general
formula:
##STR87##
wherein --X.sup.c --Y.sup.c -- represents --NH--CO-- or --CO--NH--, the
other symbols are the same meaning as defined above. This reaction is
first conducted, preferably, by converting the amide moiety of (I.sup.g)
into the imino halide group, yielding the compound (I.sup.f) where R.sup.3
is a halogen atom (e.g. Cl, Br). The reagent used in the reaction is, for
example, phosphorous halides such as phosphorous oxychloride, phosphorous
pentachloride, and thionyl halides such as thionyl chloride, thionyl
bromide, etc. The amount of the reagent is 1 to 100 mol equivalents
relative to the compound (I.sup.g). The reaction is generally carried out
in an inert solvent (e.g., ethers such as tetrahydrofurane, dioxane,
hydrocarbons such as benzene, toluene, xylene), and the reagent itself may
be used as the solvent. The reaction temperature is generally about
20.degree. C. to 200.degree. C. and preferably 50.degree. C. to
150.degree. C. The reaction time, which depends on the species of starting
compound, reagent, solvent and temperature, is generally 30 minutes to 12
hours. The imino halide thus obtained can be converted to the compounds
having various R.sup.3 -substituent, i.e., a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted amino group, a
substituted hydroxyl group, or a mercapto group substituted by an
optionally substituted hydrocarbon group. The compound (I.sup.f) where
R.sup.3 is a hydrogen atom can be prepared from (I.sup.f ;R.sup.3 .dbd.Cl,
Br) by using catalytic reduction. The reduction can be carried out by a
method similar to that used in the conversion of (I.sup.b) to (I.sup.a).
The compound (I.sup.f) where R.sup.3 is an optionally substituted amino
group can be prepared from (I.sup.f ;R.sup.3 .dbd.Cl) by reacting an
optionally substituted amine under conditions similar to those used in the
reaction of (XI) and (XII) (Method 1-ii). Similarly, the compound
(I.sup.f) where R.sup.3 is an optionally substituted hydrocarbon group, a
substituted hydroxyl group or a mercapto group substituted by an
optionally substituted hydrocarbon group can be prepared from (I.sup.f
;R.sup.3 .dbd.Cl) by reacting a Grignard reagent (e.g., MeMgBr, EtMgBr),
an alkaline metal (e.g., lithium, sodium, pottasium) salt of alchol (e.g.,
methanol, ethanol) or an alkaline metal (e.g., lithium, sodium, pottasium)
salt of thiol (e.g., methanethiol, ethanethiol), respectively, under
conditions similar to (Method 1-ii).
Of compound (I) and (I') of the present invention, a compound wherein X or
Y is a --CS-- group and/or D contains a thioxo group can be produced by
reacting a compound wherein X or Y is a --CO-- group and/or D contains an
oxo group with an appropriate sulfur containing reagents. Examples of such
reagents include phosphorus pentasulfide and Lowesson's reagent. This
reaction is normally carried out in a solvent such as dichloromethane,
chloroform, dioxane, tetrahydrofuran, benzene or toluene under water-free
conditions. The amount of sulfide used is not less than 1 mol equivalent,
preferably 2 to 5 mol equivalents, reaction temperature being between
20.degree. C. and 120.degree. C. Varying depending on kind of starting
material or sulfide, reaction temperature etc., reaction time is normally
1 to 8 hours.
When compound (I) and (I') or a salt thereof produced by the above methods
contains a lower (C.sub.1-6) alkoxy group on ring A (wherein ........ is a
double bond), ring B or the benzene ring in the group represented by Ar,
it may be converted to a hydroxyl group as necessary by reaction with, for
example, boron tribromide. This reaction is normally carried out in a
solvent (e.g., halogenated hydrocarbons such as dichloromethane,
chloroform, carbon tetrachloride, benzene and toluene, and hydrocarbons)
at about -20.degree. to 80.degree. C., preferably about 0.degree. to
30.degree. C. The amount of boron tribromide used is about 1 to 10 mol
equivalents, preferably about 1 to 5 mol equivalents per mol of lower
alkoxy group. Reaction time is normally 15 minutes to 24 hours, preferably
30 minutes to 12 hours. Also, when compound (I) and (I') or a salt thereof
produced by the above methods contains a hydroxyl group on ring A, ring B
or the benzene ring in the group represented by Ar, it may be converted to
an alkoxy or acyloxy group by alkylation or acylation as necessary. This
alkylation is carried out by a reaction with an alkylating agent such as a
halide (e.g., chloride, bromide, iodide) of an alkane which may have a
substituent or a sulfate ester or sulfonate ester (e.g., methanesulfonate,
p-toluenesulfonate, benzenesulfon-ate) in a solvent (e.g., alcohols such
as methanol, ethanol and propanol, ethers such as dimethoxyethane, dioxane
and tetrahydrofuran, ketones such as acetone and amides such as
N,N-dimethylformamide) in the presence of a base (e.g., organic bases such
as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline
and N,N-dimethylaniline, and inorganic bases such as potassium carbonate,
sodium carbonate, potassium hydroxide and sodium hydroxide). Reaction
temperature is normally -10.degree. to 100.degree. C., preferably about
0.degree. to 80.degree. C. The amount of these alkylating agents used is
about 1 to 5 mol equivalents, preferably 1 to 3 mol equivalents per mol of
starting material phenolic derivative. Reaction time is normally 15
minutes to 9.4 hours, preferably 30 minutes to 12 hours.
Acylation is carried out by using the appropriate carboxylic acid or a
reactive derivative thereof. Although varying depending on type of
acylating agent and type of starting material phenolic derivative, this
reaction is normally carried out in a solvent (e.g., hydrocarbons, ethers,
esters, halogenated hydrocarbons, amides, aromatic amines such as benzene,
toluene, ethyl ether, ethyl acetate, chloroform, dichloromethane, dioxane,
tetrahydrofuran, N,N-dimethylformamide and pyridine); appropriate bases
(e.g., hydrogen carbonates such as sodium hydrogen carbonate and potassium
hydrogen carbonate, carbonates such as sodium carbonate and potassium
carbonate, acetates such as sodium acetate, tertiary amines such as
triethylamine, aromatic amines such as pyridine) may be added to
accelerate the reaction. Such reactive derivatives of carboxylic acid
include acid anhydrides, mixed acid anhydrides and acid halides (e.g.,
chloride, bromide). The amount of these acylating agents used is 1 to 5
mol equivalents, preferably 1 to 3 mol equivalents per mol of starting
material phenolic derivative. Reaction temperature is normally about
0.degree. to 150.degree. C., preferably about 10.degree. to 100.degree. C.
Reaction time is normally 15 minutes to 12 hours, preferably 30 minutes to
6 hours.
Also, known amide compounds of formula (I) and (I') can be synthesized by,
for example, (1) the method described in the Indian Journal of Chemistry,
Section B, 26B, Vol. 8, pp. 744-747 (published 1987), (2) the method
described in the Chemical Abstract, Vol. 107, 175835f, (3) the method
described in the Chemical Abstract, Vol. 114, 42492q, (4) the method
described in the Chemical Abstract, Vol. 107, 115463y, (5) the method
described in the Chemical Abstract, Vol. 93, 220536q, a method based
thereof, or by the above-described production method for the compounds
represented by formula (I) and (I') or methods based thereon.
When compound (I) and (I') is obtained in a free form by one of the above
methods, it may be prepared as a salt with an inorganic acid (e.g.,
hydrochloric acid, sulfuric acid, hydrobromic acid), an organic acid
(e.g., methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,
oxalic acid, fumaric acid, maleic acid, tartaric acid), an inorganic base
(e.g., alkali metals such as sodium and potassium, alkaline earth metals
such as calcium and magnesium, aluminum or ammonium), or an organic base
(e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine or
N,N'-dibenzylethylenedismine). When compound (I) is obtained in the form
of a salt, it can be converted to the free form or another salt, in
accordance with a conventional method.
The thus-obtained desired compound (I) and (I') or salt thereof can be
purified and separated by a known means of separation and purification
(e.g., concentration, solvent extraction, column chromatography or
recrystallization).
Starting material (VII), or a salt thereof, used to produce the inventive
compound (I) and (I') or a salt thereof can industrially advantageously
produced by, for example, the following methods 1) to 3) or methods based
thereon.
1) Compounds represented by the general formulas:
##STR88##
wherein the symbols have the same definitions as above, or esters thereof
can be synthesized by methods (or methods based thereon) such as those
described in European Patent Publication No. 421456 (published Apr. 11,
1991), European Patent Publication No. 354994 (published Feb. 21, 1990),
European Patent Publication No. 481383 (published Apr. 22, 1992), PCT
International Patent Publication No. WO9112249 (published Aug. 22, 1991),
and Bolletino Chimico Farmaceutico, vol. 125 pp. 437-440 (published 1986,
describe dy N. A. Santagati et al.).
The compound (VII-3) can also be produced via an amide compound of (VII-3).
An amide compound of (VII-3) is produced by the method described by K.
Unverferth et al. in Archiv der Pharmazie, Vol. 324,pp. 809-814 (published
1991) or a method based thereon. This amide compound may be reacted under,
for example, diazotizing conditions (e.g., reacted with sodium nitrite at
about 0.degree. to 50.degree. C. in an acidic solvent such as acetic acid
or hydrochloric acid) to yield compound (VII-3).
2) Compounds represented by the general formulas:
##STR89##
wherein the symbols have the same definitions as above, can be synthesized
by, for example, the following methods 2-A) and 2-B) or methods based
thereon.
Method 2-A)
The carboxyl group of (VII-1) to (VII-5) is treated with diazomethane to
add one carbon atom to the carboxyl group by a reaction generally known as
the Arndt-Eistert reaction (F. Arndt et al.: Chemische Berichte, Vol. 68,
page 200 (published 1935)) to yield (VII-6) to (VII-10), respectively. For
example, a method is known wherein a compound of formula (VII-5) whose
ring A is not substituted for and whose ring B is not substituted for or
has substituent methyl for R.sup.3 in the above formula is converted to a
corresponding compound of formula (II-10) having a substituent (I. N.
Chatterjea et al.: Liebigs Ann. Chem., 1974, page 1126); by this method or
a method based thereon, (VII-6) to (VII-10) can be produced. In this
method, the desired compound may be isolated as a carboxylic acid ester
(methyl ester, ethyl ester etc.), which ester is then converted to a
carboxylic acid by hydrolysis. This hydrolyzing reaction is normally
carried out in a solvent (e.g., alcohols such as methanol, ethanol and
propanol, organic acids such as acetic acid) in the presence of an aqueous
solution of a mineral acid (e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid) or a metal hydroxide (e.g., sodium hydroxide, potassium
hydroxide) at a treatment temperature of about 15.degree. to 103.degree.
C.
Method 2-B)
One carbon atom is also added to the carboxyl group of (VII-1) to (VII-5)
by the following method:
##STR90##
wherein H represents the heterocyclic moiety of (VII-1) to (VII-10); L
represents a leaving group. In this method, the carboxyl group is first
reduced to yield an alcohol. This reduction is carried out by converting
the carboxyl group to a reactive derivative thereof (acid halide, mixed
acid anhydride, active ester, ester etc.) and then treated at a reaction
temperature of about 0.degree. to 100.degree. C. in a solvent (ether such
as tetrahydrofuran or dimethoxyethane) in the presence of a reducing agent
(sodium borohydride, lithium aluminum hydride). The hydroxyl group of the
thus-obtained alcohol is converted to a leaving group (--OH.fwdarw.--L).
The leaving group L is preferably a halogen (chlorine, bromine, iodine
etc.), a C.sub.1-4 alkanesulfonyloxy group (e.g., methanesulfonyloxy
group, ethanesulfonyloxy group) or a C.sub.6-10 arylsulfonyloxy group
(e.g., benzenesulfonyloxy group, p-toluenesulfonyloxy group). This
converting reaction is normally carried out by a treatment with, for
example, thionyl chloride, thionyl bromide, methanesufonyl chloride or
benzenesulfonyl chloride in a solvent (e.g., benzene, toluene,
dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, ethyl
acetate) at a treatment temperature of about 0.degree. to 100.degree. C.
The leaving group of the compound is then converted to a nitrile group
(--L.fwdarw.--CN). This reaction is normally carried out by a treatment
with, for a cyanogen compound such as sodium cyanide, potassium cyanide or
copper cyanide in a solvent (e.g., dimethylsulfoxide, dimethylformamide,
acetone) at a treatment temperature of 0.degree. to 100.degree. C. The
resulting nitrile compound is hydrolyzed to carboxylic acids (VII-6) to
(VII-10). This hydrolyzing reaction is normally carried out in a solvent
(alcohol such as methanol, ethanol or propanol, or acetic acid) in the
presence of an aqueous solution of a mineral acid (e.g., hydrochloric
acid, hydrobromic acid, sulfuric acid) or a metal hydroxide (e.g., sodium
hydroxide, potassium hydroxide) at a treatment temperature of about
15.degree. to 130.degree. C. Compounds (VII-6) and (VII-7) can also be
produced by the method described by H. Kohl et al. in the Journal of
Pharmaceutical Sciences, Vol. 69, page 2028 (published 1973) or a method
based thereon.
3) Compounds represented by the general formulas:
##STR91##
wherein the symbols have the same definitions as above, can be produced
from the above compounds (VII-1), (VII-3), (VII-4), (VII-5) or esters
thereof, respectively, by reducing the double bond at the positions 3 and
4 to single bond. This method can, for example, be carried out by the
above-described method used to convert (I.sup.a) to (I.sup.b) or a method
based thereon. When an ester is used as the starting material, esters of
(VII-11) to (VII-14) are produced, which may be hydrolyzed as described in
Method 2-A) to carboxylic acids. Compound (VII-11) or an ester thereof can
also be produced using a reducing agent such as lithium aluminum hydride.
This reaction is normally carried out in a solvent (ethers such as
tetrahydrofuran, dioxane and dimethoxyethane) at a temperature of about
0.degree. to 100.degree. C.
4) A compound represented by the general formula:
##STR92##
wherein the symbols have the same definitions as above, can be produced
from, for example, compound (VII-2A) by the following method:
##STR93##
wherein R' represents a lower alkyl group (e.g. methyl, ethyl, etc.), the
other symbols having the same definitions as above.
In this method, (VII-2A) is first reduced, at the positions 1 and 4, to a
1,4-dihydro derivative. This reducing reaction is carried out using a
reducing agent such as sodium borohydride or sodium cyanoborohydride. The
reaction is normally carried out in a solvent (alcohols such as methanol,
ethanol and propanol, ethers such as tetrahydrofuran, dioxane and
dimethoxyethane) at a temperature of about 15.degree. to 100.degree. C.
The position 1 of this 1,4-dihydro derivative is then alkylated by a
reaction with an alkylating agent represented by the general formula R'--L
(the symbols have the same definitions as above). The alkylating reaction
is normally carried out in a solvent (ethers such as tetrahydrofuran,
dioxane and dioxane, amides such as dimethylformamide), preferably in the
presence of a base (e.g., sodium hydride, potassium hydride, sodium
methylate, sodium ethylate, sodium amide, potassium t-butoxide). The
reaction is normally carried out at a temperature of about -10.degree. to
100.degree. C. The thus-obtained 1-alkyl-1,4-dihydro derivative is reduced
to a 1,2,3,4-tetrahydro derivative (VII-15A). This reducing reaction is
carried out using a reducing agent such as sodium cyanoborohydride, sodium
borohydride or lithium aluminum hydride. The reaction is normally carried
out in a solvent at a temperature of about 0.degree. to 100.degree. C.
Varying depending on the kinds of reducing agent and substrate used, it is
possible to use the same solvents as used in the above-described reducing
reaction of (VII-2A) to 1,4-dihydro derivative. Conversion of (VII-15A) to
(VII-15) is achieved by a hydrolyzing reaction as described in Method
2-A).
5) Compounds represented by the general formulas:
##STR94##
wherein the symbols have the same definitions as above, can be produced
from the above-mentioned compounds (VII-11) to (VII-15) by adding one
carbon atom. This method can be carried out in the same manner as the
above-described Method 2-A) or 2-B) or a method based thereon. (VII-16)
and (VII-19) can also be produced by the following method:
##STR95##
wherein X.sup.0 represents --NR.sup.1a -- (R.sup.1a represents the same
meaning as defined hereinabove) or --O--; R" and R'" independently
represent a protecting group for the carboxyl group; the other symbols
have the same definitions as above.
With respect to the above formula, the carboxyl group protecting groups R"
and R'" is exemplified by ester-forming protecting groups such as methyl,
ethyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, tert-butyl,
benzyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl and allyl, and
silyl-ester-forming protective groups such as trimethylsilyl,
triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl and
dimethylphenylsilyl. In the above method, the position 3 of (VII-11A) or
(VII-13A) is first alkylated with an alkylating agent represented by the
general formula R'"OCOCH.sub.2 -L (the symbols have the same definitions
as above). This reaction can be carried out under the same conditions as
for the position 1 alkylation in 4) above. The resulting alkyl derivative,
after removal of the protecting group R", may be decarboxylated to
(VII-16A) or (VII-19A). Varying depending on the type of protecting group
used, the protecting group R" can be removed by hydrolysis by the method
described in Method 2-A) above when R" is a lower alkyl group such as
methyl or ethyl. In this case, when R'" is similarly a lower alkyl group
such as methyl or ethyl, it may also be removed to leave and isolate a
dicarboxylic acid. While heating, the R"-removed carboxylic acid may be
further decarboxylated to yield compound (VII-16A) or (VII-19A). In the
case of a dicarboxylic acid wherein both R" and R'" have been removed,
this decarboxylation immediately results in the production of (VII-16) or
(VII-19). This decarboxylation is normally carried out in a solvent (e.g.,
pyridine, picoline, benzene, toluene, dimethylsulfoxide,
dimethylformamide, acetic acid) at a temperature of about 40.degree. to
200.degree. C. The thus-obtained compounds (VII-16A) and (VII-19A) can be
converted to compounds (VII-16) and (VII-19), respectively, by removing
their R'" by a deprotecting reaction according to the type thereof.
6) A compound represented by the general formula:
##STR96##
wherein X.sup.d represents --NR.sup.1a -- (R.sup.1a represents the same
meaning as defined hereinabove), --O-- or --S--; Z" represents --CR.sup.4a
-- (R.sup.4a is an optionally substituted hydrocarbon group) or --N--; the
other symbols have the same definitions as above, is produced by
alkylating a compound represented by the general formula:
##STR97##
wherein the symbols have the same definitions as above, with the
alkylating agent used above 5), represented by the formula R'"OCOCH.sub.2
-L, and then removing the protecting group R'". The alkylating and
deprotecting reactions can be carried out under the same conditions as
described above.
7) Compounds (VII'-23) and (VII'-24), represented by the general formula:
wherein the symbols have the some definitions as above, and having
--NR.sup.1a -- for X.sup.d and hydrogen for at least one of R.sup.2 and
R.sup.2a, can be produced by the following method:
##STR98##
wherein the symbols have the same definitions as above. In this method,
(VII-2A) or (VII-7A) is first alkylated to a quaternary salt, which is
then reduced to a 1,2-dihydro derivative (VII-23A) or (VII-24A),
respectively. This converting reaction can be carried out in the same
manner as the converting reaction of compound
(I.sup.d).fwdarw.(I.sup.e).fwdarw.(I.sup.c). The thus-obtained compounds
(VII-23A) and (VII-24A) may be subjected to the above-described Method
2-A) to remove R' to yield (VII-23) and (VII-24), respectively.
Alternatively, (II-23) can be produced by the following method:
##STR99##
wherein the symbols have the same definitions as above. In this method, a
benzophenone derivative, as the starting material, is reacted with, for
example, a propionic acid derivative represented by the following formula:
##STR100##
wherein the symbols have the same definitions as above, to a substituted
benzophenone derivative. Upon dehydrating reaction, this compound yields a
cyclized derivative (VII-23A). (VII-23A) may be subjected to the
above-described Method 2-A) to remove R' to yield (VII-23).
(VII-23) may be subjected to the above-described Method 2-A) or 2-B) to add
one carbon atom to yield (VII-24).
8) Compounds represented by the general formula:
##STR101##
wherein the symbols have the same definitions as above, and having S for
X.sup.d, hydrogen for each of R.sup.2 and R.sup.2a and 0 for p, include
known compounds; for example, Natsugari et al. describe in European Patent
Publication No. 481383 (published Apr. 22, 1992) a method of synthesizing
these compounds as intermediates. Another compound (VII-25) wherein
p.dbd.0 can also be produced in accordance with this method. (VII-25) may
be treated in the same manner as the above-described Method 2-A) or 2-B)
to add one carbon atom to yield (VII-26).
9) A compound represented by the general formula:
##STR102##
wherein the symbols have the same definitions as above, can be produced
from, for example, compounds of formulas (VII-6) to (VII-10), (VII-16) to
(VII-22), (VII-24) and (VII-26) by adding one carbon atom by the
above-described reaction Method 2-A) or 2-B).
10) In accordance with the above-described methods 1) through 3), 5) and
9), compounds of general formula (VII) wherein either X' or Y'-- is S, the
other being --CO--, can be produced. Also, compounds of general formula
(VII) wherein either X' or Y' is --CO-- can be converted to those wherein
either is --CS-- by a thioxo-derivatizing reaction with phosphorus
pentasulfide etc.
11) A compound represented by the general formula:
##STR103##
wherein .alpha. represents an integra from 1 to 3, the other symbols
representing the same definition as above, can be produced from the
corresponding carboxylic acid by subjecting reduction as described in
Method 2B).
12) A compound represented by the general formula:
##STR104##
wherein the symbols represent the same definition as above can be produced
from the corresponding hydroxyl compound (XIV) by subjecting the
conversion (--OH.fwdarw.--L) reaction described in Method 2B).
13) A compound represented by the general formula:
##STR105##
wherein the symbols represent the same definition as above can be produced
from (XV) by reacting an amine represented by the formula R.sup.5
--NH.sub.2 (the symbols have the same definition as above). This reaction
can be carried out using the same conditions as those described in the
alkylation reaction of (II) with (III) (Method 1-ii).
When the substituent in these compounds thus prepared contains a functional
group, it can be converted to another appropriate functional group by
various known methods. For example, when the substituent is a group
containing a carboxyl group or ester thereof, it can be converted to an
amide group by reaction with, for example, an amine or to a hydroxymethyl
group or another group by reduction, for a starting material for synthesis
of compound (I) and (I').
Starting materials for production of compound (I-A) or a salt thereof
include compounds represented by the formulas (S-1) and (S-2). These
compounds can be produced by the method schematized in the following
reaction scheme 1 or a method based thereon.
##STR106##
wherein P.sup.1 and P.sup.2 independently represent a protecting group for
the carboxyl group; t represents an integer from 2 to 4; the other symbols
have the same definitions as above.
With respect to the above formulas, the carboxyl group protecting groups
P.sup.1 and P.sup.2 are exemplified by ester-forming protecting groups
such as methyl, ethyl, methoxymethyl, methoxyethoxymethyl,
benzyloxymethyl, tert-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl,
o-nitrobenzyl, benzhydryl, trityl, 2,2,2-trichloroethyl,
2-trimethylsilylethyl and allyl, and silyl-ester-forming protective groups
such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and
isopropyldimethylsilyl.
In the above method, compound (S-a) is first intramolecularly cyclized to
compound (S-b). This cyclization is carried out by a reaction generally
known as Dieckmann Condensation ›J. P. Schaefer et al.: Organic Reactions,
Vol. 15, pp. 1-203 (published 1967)! in a solvent inert to the reaction
(e.g., tetrahydrofuran, dioxane, dimethoxyethane) in the presence of a
base (e.g., sodium hydride, sodium ethoxide, sodium methoxide, sodium
amide, potassium tert-butoxide). The amount of base used is not less than
1 mol equivalent, preferably 1.5 to 3 mol equivalents per mol of (S-a),
reaction temperature being between about 0.degree. C. and 130.degree. C.
Varying depending on type of starting material compound, reaction
temperature and other factors, reaction time is normally about 0.5 to 5
hours.
The protected carboxyl group of compound (S-b) is removed to yield ketone
compound (S-c). This reaction can be carried out under various sets of
conditions depending on type of the protecting group P.sup.1 used; when
P.sup.1 is a lower alkyl group such as methyl or ethyl, acidic or alkaline
hydrolytic conditions are preferably used, under which decarboxylation
usually takes place simultaneously with the removal of P.sup.1, yielding
compound (S-c). This reaction is carried out in a solvent (e.g., alcohols
such as methanol, ethanol and propanol, ethers such as tetrahydrofuran,
dioxane and dimethoxyethane, and mixtures thereof) under alkaline
conditions with an alkali such as sodium hydroxide or barium hydroxide or
an alkaline earth metal hydroxide or under acidic conditions with an
inorganic acid such as hydrochloric acid, bromic acid or sulfuric acid or
with an organic acid such as formic acid or acetic acid, or a mixture of
these acids. Reaction temperature is normally about 0.degree. to
150.degree. C., preferably about 15.degree. to 110.degree. C., reaction
time being about 0.5 to 24 hours, preferably about 1 to 10 hours.
Conversion of compound (S-c) to amino compound (S-1) is preferably achieved
by a method of oxime derivative reduction. In this method, compound (S-c)
is first reacted with hydroxylamine to yield an oxime compound by a
conventional method (e.g., reacted at 20.degree. to 70.degree. C. in
ethanol in the presence of hydroxylamine hydrochloride and sodium
acetate). This oxime compound is then reduced to compound (S-1). This
reducing reaction is carried out by, for example, the method described by
C. A. Buehler et al. in the Survey of Organic Syntheses, pp. 423-424
(1970, published by Wiley-Interscience). For example, a reducing reaction
with zinc powder is conducted under acidic conditions (e.g., in acetic
acid solvent) or basic conditions (e.g., in a mixed solvent of ethanol and
aqueous ammonia in the presence of ammonium acetate).
Hydroxyl compound (S-2) is produced by reducing compound (S-c). For this
reducing reaction, a reducing agent such as sodium cyanoborohydride or
sodium borohydride is preferably used. The reaction is carried out in a
solvent (e.g., methanol, ethanol, tetrahydrofuran, dioxane,
dimethoxyethane) at a temperature of about 0.degree. to 50.degree. C., the
reaction time being about 15 minutes to 5 hours.
Each of the above compounds thus prepared as the starting material may form
a salt. Such salts include those with inorganic acids (e.g., hydrochloric
acid, phosphoric acid, hydrobromic acid, sulfuric acid) and those with
organic acids (e.g., acetic acid, formic acid, propionic acid, fumaric
acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid,
oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).
When these compounds have an acidic group such as --COOH, they may form a
salt with an inorganic base (e.g., alkali metal or alkaline earth metals
such as sodium, potassium, calcium and magnesium, ammonia) or with an
organic base (e.g., tri-C.sub.1-3 alkylamines such as triethylamine).
The compounds obtained by the above methods may be purified and collected
by known methods of purification such as concentration, liquid phase
conversion, re-dissolution, solvent extraction, column chromatography,
crystallization and recrystallization, or may be used in the form of a
mixture as such for the subsequent reaction.
When the starting material compound used in the above reactions contains an
amino group, a carboxyl group or a hydroxyl group as a substituent, these
groups may have incorporated a protecting group generally used in peptide
chemistry and other fields; the desired compound can be obtained by
removing the protecting group as necessary after completion of the
reaction.
Amino group protecting groups include C.sub.1-6 alkylcarbonyl groups which
may have a substituent (e.g., formyl, methylcarbonyl, ethylcarbonyl),
phenylcarbonyl groups, C.sub.1-6 alkyl-oxycarbonyl groups (e.g.,
methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl groups (e.g.,
benzoxycarbonyl), C.sub.7-10 aralkyl-carbonyl groups (e.g.,
benzyloxycarbonyl), trityl and phthaloyl. Substituents for these
protecting groups include halogen atoms (e.g., fluorine, chlorine,
bromine, iodine), C.sub.1-6 alkyl-carbonyl groups (e.g., methylcarbonyl,
ethylcarbonyl, butylcarbonyl) and nitro groups, the number of substituents
being 1 to 3.
Carboxyl group protecting groups include C.sub.1-6 alkyl groups which may
have a substituent (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,
tert-butyl), phenyl, trityl and silyl. Substituents for these protecting
groups include halogen atoms (e.g., fluorine, chlorine, bromine, iodine),
C.sub.1-6 alkylcarbonyl groups (e.g., formyl, methylcarbonyl,
ethylcarbonyl, butylcarbonyl) and nitro groups, the number of substituents
being 1 to 3.
Hydroxyl group protecting groups include C.sub.1-6 alkyl groups which may
have a substituent (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,
tert-butyl), phenyl groups, C.sub.7-10 aralkyl groups (e.g., benzyl),
C.sub.1-6 alkylcarbonyl groups (e.g., formyl, methylcarbonyl,
ethylcarbonyl), phenyloxycarbonyl groups (e.g., benzoxycarbonyl),
C.sub.7-10 aralkyl-carbonyl groups (e.g., benzyloxycarbonyl), pyranyl
groups, furanyl groups and silyl groups. Substituents for these protecting
groups include halogen atoms (e.g., fluorine, chlorine, bromine, iodine),
C.sub.1-6 alkyl groups, phenyl groups, C.sub.7-10 aralkyl groups and nitro
groups, the number of substituents being 1 to 4.
Protecting groups can be removed by known methods or those based thereon,
including treatments with acids, bases, reducing agents, ultraviolet rays,
hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,
tetrabutylammonium fluoride, palladium acetate etc.
The thus-obtained compound (I) and (I') can be isolated and purified by
ordinary means of separation such as recrystallization, distillation and
chromatography. When compound (I) and (I') is obtained as a free form, it
can be converted to a salt by a known method or a method based thereon
(e.g., neutralization). Contrarily, when it is obtained as a salt, it can
be converted to a free form or another salt by a known method or a method
based thereon.
When compound (I) and (I') has a chiral center(s), it can be resolved to d-
and 1-configurations by conventional methods of optical resolution.
The compound (I) and (I') or a salt thereof is low in acute toxicity (Mice
are dosed at 300 mg/kg, p.o. and 100 mg/kg, i.p. for observation of acute
toxic sympotoms or autonomic effects during the subsequent 72 hours; the
response is no effect) and chronic toxicity, thus being a medicinally
useful and safe substance.
The compounds (I) and (I') or a pharmacologically acceptable salt thereof
(e.g., the above-mentioned salts with inorganic or organic bases and salts
with inorganic or organic acids) exhibit excellent inhibitory action
against acyl-CoA:cholesterol acyl transferase (ACAT), and is
pharmaceutically safe with low acute and chronic toxicities. ACAT, an
enzyme involved in the higher fatty acid esterification of cholesterol in
cells, is known to play a key role in cholesterol ester absorption in the
digestive tract and cholesterol ester accumulation in various peripheral
organs and cells (e.g., arterial walls, macrophages). ACAT-inhibiting
substances can therefore inhibit intestinal absorption of food
cholesterols to suppress blood cholesterol level rise and suppress
intracellular cholesterol ester accumulation in arteriosclerosis lesions,
thus preventing progress of atherosclerosis. The objected compounds or
salt thereof of the present invention, exhibiting such excellent
ACAT-inhibitory action and excellent cholesterol-lowering activity, is
therefore useful as a safe preventive/therapeutic agent for
hypercholesterolemia, atheromatous arteriosclerosis and diseases
associated therewith (e.g. ischemic diseases such as myocardial infarction
and cerebrovascular diseases such as cerebral infarction and cerebral
stroke) in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs,
horses, bovines, sheep, monkeys, humans).
Also, the compounds (I) and (I') or salt thereof include those which
exhibit suppressing action against lipid peroxide production (antioxidant
action) (e.g., compound of the above formula wherein at least one of rings
A, B and Ar is a benzene ring substituted by an amino or hydroxyl group
which may be substituted by a C.sub.1-4 alkyl group). Lipid peroxidation
in vivo is known to be closely associated with the onset of
arteriosclerosis and ischemic diseases in the brain and cardiovascular
system. Accordingly, the objected compound (I) and (I') or salt thereof,
which exhibits both ACAT inhibitory and antioxidant actions, is highly
useful as a pharmaceutical, because it can prevent and treat various
vascular lesions due to these changes for both blood cholesterol and
peroxide lipid.
When the compounds (I) and (I') or a pharmacologically acceptable salt
thereof is used as a pharmaceutical as described above, it can be orally
or non-orally administered in the form of powder, fine subtilaes,
granules, tablets, capsules, injectable solutions or other dosage forms by
conventional methods in a mixture with appropriate pharmacologically
acceptable carriers, excipients (e.g., starch, lactose, sucrose, calcium
carbonate, calcium phosphate), binders (e.g., starch, gum arabic,
carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,
alginic acid, gelatin, polyvinylpyrrolidone), lubricants (e.g., stearic
acid, magnesium stearate, calcium stearate, talc), disintegrating agents
(e.g., carboxymethyl cellulose calcium, talc), diluents (e.g.,
physiological saline) and other additives. However, for inhibiting
cholesterol absorption, oral administration is preferred. Varying
depending on type of the objected compound or salt thereof, route of
administration, symptoms, patient's age etc., daily dose is about 0.005 to
50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg
per kg body weight for oral administration in adult hypercholesterolemia
patients. This daily dose is preferably administered in one to three
portions.
The compounds (I) and (I') of the present invention or a salt thereof
exhibit excellent ACAT-inhibitory action and excellent
cholesterol-lowering activity. The results of a pharmacologic test thereof
are given below.
The following data of (I) to (III) are the experimental data showing the
pharmacological efficacy of the compound (I) and (I') or salts thereof of
the present invention.
(I) Inhibitory Action Against Acyl-CoA:cholesterol Acyl Transferase (ACAT)
Method of Experiment
An ACAT enzyme preparation was prepared from a small intestine mucosal
microsome fraction of a 6-week-old male Sprague-Dawley rat, previously
fasted for 20 hours, in accordance with the method described by Heider et
al. in the Journal of Lipid Research, Vol. 24, page 1127 (1982).
ACAT activity was determined by measuring the amount of labeled cholesterol
ester produced from ›1-.sup.14 C!-oleoyl-CoA and endogenous cholesterol,
in accordance with the method of Helgerud et al. ›Journal of Lipid
Research, Vol. 22, page 271 (1981)!.
Results
(1) Table 1 shows data on the inhibitory rate (%) of formation of labeled
cholesterol ester inhibitory rate (%), as an index of ACAT-inhibitory
action, obtained when the compound was added at 10.sup.-6 M.
TABLE 1
______________________________________
Subject Compound
ACAT Inhibitory Rate (%)
(Example No.) 10.sup.-6 M
______________________________________
9 90.3
10 93.3
13 93.8
15 90.2
18 97.3
19 99.1
20 97.8
21 99.3
22 97.9
23 99.4
25 96.9
27 92.0
29 98.4
31 97.5
32 96.0
33 98.9
36 98.8
42 96.6
43 98.2
45 99.5
47 90.3
48 99.2
49 92.8
50 95.7
51 98.1
52 90.4
53 99.7
54 98.4
55 97.9
56 98.1
57 99.3
60 99.9
64 99.5
74 99.5
76 99.3
79 99.1
82 99.3
83 99.4
84 99.5
85 99.5
87 99.3
88 99.7
89 98.2
92 98.2
93 99.0
94 98.6
95 99.1
96 99.3
99 97.0
______________________________________
Table 1 shows that compound (I) or a salt thereof exhibits excellent
ACAT-inhibitory action.
(II) Hypocholesterolemic Activity
(Cholesterol-lowering Activity)
Method of Experiment
Groups of 6 ICR mice (2 subgroups of 3 mice) were made hypercholesterolemic
by being fed a high cholesterol-cholic acid diet for 7 days and
administered with test compounds orally on the last two days. One-half of
the total does was given on day 6 followed by the other half on day 7.
After fasting overnight (16 hours after the last dose), the animals were
sacrificed and sera were collected together for the each subgroup for
measuring the levels of cholesterol and heparin precipitating lipoproteins
(HPL). Both cholesterol and HPL levels were measured with autonalyzer by
the enzymatic CHOD-PAP method for the former and by the turbidimetric
method of Shurr et. al. ›in C. E. Dau ed. Atherosclerosis Drug Discovery,
Plenum Publishing, New York, pp. 215-229 & 231-249, 1976.! for the latter.
Table 2 shows reduction % (compared to control groups) of cholesterol and
HPL.
Results
TABLE 2
______________________________________
Test compounds
Dose (po) Reduction %
(Example No.)
mg/kg cholesterol
HPL
______________________________________
48 10 32 39
3 27 26
74 10 33 37
3 29 32
82 10 40 50
3 31 37
84 10 33 47
3 15 28
______________________________________
From Table 2, it is clear that compound (I) or a salt thereof exhibits
excellent hypocholesterolemic activity.
Also, the compounds (I) and (I') and a salt thereof according to the
invention has excellent tachykinin receptor antagonizing activity,
particularly potent antagonistic activity against substance P (hereinafter
sometimes referred to briefly as SP), and is low in acute toxicity and
chronic toxicity, thus being a medicinally useful and safe substance.
Substance P (SP) is a neuropeptide discovered in an equine intestinal canal
extract in 1981 and its structure, consisting of 11 amino acids, was
established in 1971. SP is broadly distributed in the central and
peripheral nervous systems and, in addition to being a primary sensory
neurotransmitter, has various physiological activities such as
vasodilating activity acugmentation of vascular permeability, smooth
muscle contracting activity, neuronal excitatory activity, sialogogue
activity, facilitation of micturition and immunomodulatory effect. It is
known particularly that SP released by a pain impulse at the terminal of
the cornu posterius of the spinal cord transmits pain information to
secondary neurons and that SP released from the peripheral nerve terminal
induces an inflammatory response in the nociceptive field. Moreover, SP is
suspected to be involved in Alzheimer type dementia. Therefore, the
objected compounds or salts thereof having potent SP receptor antagonizing
activity are of value as a safe prophylactic/therapeutic drug for pain,
inflammation, allergy airway diseases such as asthma and cough,
disturbances of micturition such as pollakiuria and incontinence dementia
in mammalian animals (e.g. mouse, rat, hamster, rabbit, cat, dog, bovine,
sheep, monkey, man, etc.).
The dosage is dependent on the species of the objected compound or salts
thereof, route of administration, disease condition, and patient's age and
other background factors. However, for oral administration to an adult
patient, for instance, a daily dose of about 0.0015 to 50 mg, preferably
about 0.05 to 10 mg, more preferably about 0.2 to 4 mg, per kg body weight
is administered in 1 to 8 divided doses.
(III) Radioligand Receptor Binding Inhibitory Assay Using Receptor From
Human Lymphoblast Cells (IM-9)
The method of A. Margaret et al. ›Molecular Pharmacology 42, 458 (1992)!
was modified and used. The receptor was prepared from human lymphoblast
cells (IM-9). IM-9 cells were grown in 175 cm.sup.2 tissue culture flasks
(100 ml.times.10) at a density approximately 2.times.10.sup.5 /ml of RPMI
1640 with L-glutamine, 10% (V/V) heat inactivated fetal calf serum,
penicillin (100 u/ml), and streptomycin (100 .mu.g/ml) at 37.degree. C. in
5% CO.sub.2 /95% air for 3 days. IM-9 cells were obtained by
centrifugation at 500 Xg for 5 minutes at 5.degree. C. The pellet obtained
was washed once with phosphate buffer (Flow Laboratories, CAT No.
28-103-05), homogenized using Polytron homogenizer (Kinematika, Germany)
in 30 ml of 50 mM Tris-HCl buffer containing 120 mM NaCl, 5 mM KCl, 2
.mu.g/ml phenylmethyl sufonyl fluoride, and 1 mM ethylenediamine
tetra-acetic acid and then centrifuged at 40,000 Xg for 20 minutes. The
residue was washed twice with 30 ml of buffer described above, and
preserved frozen (-80.degree. C.).
The above specimen was suspended in a reaction buffer (50 mM Tris-HCl
buffer (pH 7.4), 0.02% bovine serum albumin, 1 mM phenylmethylsulfonyl
fluoride, 2 .mu.g/ml chymostatin, 40 .mu.g/ml bacitracin, 3 mM manganese
chloride) at a protein concentration of 1.5 mg/ml and a 100 .mu.l portion
of the suspension was used in the reaction. After addition of the sample
and 125I-BHSP (0.46 KBq), the reaction was conducted in 0.2 ml of reaction
buffer at 25.degree. C. for 30 minutes. The amount of nonspecific binding
was determined by additing substance P at a final concentration of
2.times.10.sup.-6 M. After the reaction, using a cell harvester (290PHD,
Cambridge Technology, Inc., England), rapid filtration was carried out
through a glass filter (GF/B, Whatman, U.S.A.) to stop the reaction. After
washing three times with 250 .mu.l of 50 mM Tris-HCl buffer (pH 7.4)
containing 0.02% bovine serum albumin, the radioactivity remaining on the
filter was measured with a gamma counter. Before use, the filter was
immersed in 0.1% polyethyleneimine for 24 hours and air-dired.
The antagonistic activity of each test substance, in terms of the
concentration necessary to cause 50% inhibition ›IC.sub.50 ! under the
above conditions, was expressed in nM (Table 3).
TABLE 3
______________________________________
Test Compounds
Example No. IC50 (nM)
______________________________________
101 2.5
102 1.3
103 34
104 16
105 19
106 30
107 34
108 30
109 50
110 90
111 98
112 8.4
122 82
123 46
127 8.8
128 88
130 38
131 86
156 6.1
157 1.2
158 78
159 12
165 24
166 0.35
170 19
171 20
172 0.5
173 24
174 3.4
175 6.2
176 0.7
177 13
178 0.14
179 80
180 9.1
181 31
182 2
184 17
185 32
186 1.8
187 1.4
188 1.2
189 1.7
190 13
191 28
205 22
207 110
208 140
211 23
212 30
216 62
218 23
221 130
224 68
225 94
233 44
239 80
240 2
241 60
242 8.6
243 0.9
244 1.6
245 59
246 0.61
247 5.2
248 16
249 17
250 0.9
251 60
254 0.36
255 1.3
256 4.4
258 3.1
260 1
261 63
262 2
263 46
264 16
265 0.52
266 8.2
267 0.68
269 1.4
270 10
271 1.9
272 23
273 2
274 2.3
275 1.9
276 3
277 54
278 10
279 34
280 58
281 36
282 22
285 9.4
______________________________________
It is apparant from Table 3 that the objected compound and salts thereof of
the present invention have excellent substance P receptor antagonizing
actitity.
›EXAMPLES !
The present invention is hereinafter described in more detail by means of
the following reference examples and working examples. The following
Reference Examples and Examples are further descriptive of the present
invention. It should be understood that these are merely illustrative and
by no means definitive of the invention and that many changes and
modifications can be made within the scope of the invention.
Elution in column chromatography in the reference and working examples was
conducted with observation by TLC (Thin Layer Chromatography), unless
otherwise stated. In the TLC observations, a TLC plate of Merck
60F.sub.254 was used, in which the developing solvent was the same as the
column chromatography eluent and the detector was a UV detector. Silica
gel used for column chromatography was Merck Silica gel 60 (70-230 mesh).
Room temperature is generally defined to be between about 10.degree. C.
and 35.degree. C.
Extracts were dried over sodium sulfate or magnesium sulfate.
The abbreviations in the working and reference examples are defined as
follows:
DMF for dimethylformamide, THF for tetrahydrofuran, DMSO for dimethyl
sulfoxide, Hz for Herz, J for coupling constant, m for multiplet, q for
quartet, t for triplet, d for doublet, s for singlet and b for broad.
EXAMPLE 1
6-Chloro-N-(2,4-difluorophenyl)-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxamid
Method A
To a solution of 6-chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid
(450 mg) in dichloromethane (20 ml) were added oxalyl chloride (0.22 ml)
and DMF (one drop) at room temperature, followed by stirring for 1 hour.
After the solvent was distilled off, the residue was dissolved in
anhydrous THF (20 ml). To this solution was added a solution of
2,4-difluoroaniline (0.30 ml) and triethylamine (0.27 ml) in anhydrous
THF, followed by stirring at room temperature for 1.5 hours. After the
solvent was distilled off, ethyl acetate was added to the residue, which
was then washed successively with water, dilute hydrochloric acid, water,
aqueous sodium hydrogen carbonate and water and then dried, after which
the solvent was distilled off, to yield the title compound as colorless
crystals (520 mg).
Method B
To a solution of 6-chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid
(300 mg) in 1,2-dichloroethane (10 ml) were added 1-hydroxybenzotriazole
(135 mg) and 1,3-dicyclohexylcarbodiimide (220 mg), followed by stirring
at room temperature for 0.5 hours. To this mixture was added
2,4-difluoroaniline (0.20 ml), followed by stirring at room temperature
for 16 hours. After the reaction mixture was concentrated, ethyl acetate
was added to the residue, and the precipitated crystals were separated by
filtration. The filtrate was washed successively with dilute hydrochloric
acid, water, aqueous potassium carbonate and water and then dried, after
which the solvent was distilled off, to yield the title compound as
colorless crystals (350 mg).
Melting point: 189.degree.14 191.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 6.70-6.93 (2H,m), 7.08
(1H,d, J=2.2 Hz), 7.24-7.63 (6H,m), 8.10 (1H,m), 8.39 (1H,d,J=8.6 Hz),
8.68 (1H,b)
Elemental analysis (for C.sub.22 H.sub.12 NO.sub.3 ClF.sub.2): Calculated
(%): C, 64.17; H, 2.94; N, 3.40 Found (%): C, 63.91; H, 2.84; N, 3.44
In the working examples 2 to 97 below, unless otherwise specified, the
desired compound was obtained in substantially the same method as Method A
or Method B in Example 1, using the carboxylic acid and aniline
corresponding thereto as starting materials. For the compounds of
respective examples, the method of synthesis (Method A or Method B) is
specified with (A) or (B) after the name of the compound.
EXAMPLE 2
4-(4-Fluorophenyl)-6-methyl-1-oxo-N-(2,4,6-trimethoxyphenyl)-1H-2-benzopyra
n-3-carboxamide (A)
Melting point: 228.degree.-229.degree. C. (recrystallized from ethanol) NMR
(200 MHz, CDCl.sub.3) ppm: 2.39 (3H,s), 3.76 (6H,s), 3.77 (3H,s), 6.10
(2H,s), 6.88 (1H,s), 7.10-7.30 (4H,m), 7.44 (1H,d,J=8.0 Hz), 7.90 (1H,s),
8.31 (1H,d,J=8.0 Hz)
Elemental analysis (for C.sub.26 H.sub.22 NO.sub.6 F): Calculated (%): C,
67.38; H, 4.78; N, 3.02 Found (%): C, 67.21; H, 4.92; N, 3.13
EXAMPLE 3
N-(2,4-Difluorophenyl)-4-(4-fluorophenyl)-6-(
1-methylethyl)-2-oxo-2H-1-benzopyran-3-carboxamide (A)
Melting point: 175.degree.-176.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR(200 MHz, CDCl.sub.3) ppm: 1.17 (6H,d,J=7.0
Hz), 2.87 (1H,m), 6.70-6.90 (2H,m), 6.96 (1H,d, J=2.0 Hz), 7.18-7.57
(6H,m), 8.12 (1H,m), 9.74 (1H,b)
Elemental analysis (for C.sub.25 H.sub.18 NO.sub.3 F.sub.3): Calculated
(%): C, 68.65; H, 4.15; N, 3.20 Found (%): C, 68.68; H, 4.00; N, 3.14
EXAMPLE 4
N-›2,6-Bis(1-methylethyl)phenyl!-4-(4-fluorophenyl)-6-(1-methylethyl)-2-oxo
-2H-1-benzopyran-3-carboxamide (A)
Melting point: 220.degree.-222.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.11 (12H,d,J=6.8 Hz), 1.18
(6H,d,J=6.8 Hz), 2.87 (1H,m), 2.97 (2H,m), 6.97 (1H,d, J=1.4 Hz),
7.10-7.55 (9H,m), 8.18 (1H,b)
Elemental analysis (for C.sub.31 H.sub.32 NO.sub.3 F): Calculated (%): C,
76.68; H, 6.64; N, 2.88 Found (%): C, 76.30; H, 6.60; N, 2.84
EXAMPLE 5
N-›2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methy
lethyloxy)-3-quinolinecarboxamide (A)
Melting point: 176.degree.-178.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.04 (12H,bs), 1.46
(3H,d,J=6.4 Hz), 1.51 (3H,d,J=6.2 Hz), 2.26 (3H,s), 2.43 (3H,s), 2.60-3.80
(2H,bs), 5.78 (1H,m), 6.82 (1H,s), 7.00-7.65 (8H,m), 7.67 (1H,s)
Elemental analysis (for C.sub.33 H.sub.37 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 74.91; H, 7.05; N, 5.29 Found (%): C, 74.98; H, 7.09; N, 5.35
EXAMPLE 6
4-›3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl!-N-›2,6-bis(1-methylethyl)ph
enyl!-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinecarboxamide (A)
Melting point: 334.degree.-338.degree. C. (recrystallized from
acetone-methanol) NMR (200 MHz, CDCl.sub.3) ppm: 1.24 (12H,d,J=7.0 Hz),
1.64 (18H,s), 2.35 (1H,s), 2.74 (1H,m), 3.97 (3H,s), 5.59 (1H,s),
7.09-7.13 (1H,m), 7.29-7.50 (5H,m), 7.67-7.73 (2H,m), 8.66-8.71 (1H,m)
Elemental analysis (for C.sub.37 H.sub.46 N.sub.2 O.sub.3 .cndot.1/4H.sub.2
O): Calculated (%): C, 77.79; H, 8.20; N, 4.90 Found (%): C, 77.75; H,
8.22; N, 4.75
EXAMPLE 7
N-›2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-1-ethyl-6,7-dimethyl-2-
oxo-3-quinolinecarboxamide (A)
Melting point: 217.degree.-222.degree. C. (recrystallized from
acetone-hexane) NMR (200 MHz, CDCl.sub.3)ppm: 1.11 (12H,d,J=6.2 Hz), 1.50
(3H,t,J=7.2 Hz), 2.19 (3H,s), 2.44 (3H,s), 3.10 (2H,bs), 4.38-4.68 (2H,m),
6.79 (1H,s), 7.02-7.50 (8H,m), 9.79 (1H,s)
Elemental analysis (for C.sub.32 H.sub.35 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 74.62; H, 6.85; N, 5.44 Found (%): C, 74.70; H, 7.06; N, 5.41
EXAMPLE 8
N-(2,5-Dimethoxyphenyl)-4-(4-fluorophenyl)-1-oxo-1H-2-benzopyran-3-carboxam
ide (A)
Melting point: 186.degree.-187.degree. C. (recrystallized from
acetone-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.72 (3H,s), 3.90
(3H,s), 6.59 (1H,dd,J=12.0, 3.0 Hz), 6.81 (1H,d,J=8.8 Hz), 7.10-7.30
(5H,m), 7.60-7.72 (2H,m), 7.96 (1H,d,J=2.8 Hz), 8.44 (1H,dd,J=7.2, 1.0
Hz), 9.23 (1H,b)
Elemental analysis (for C.sub.24 H.sub.18 O.sub.5 F): Calculated (%): C,
68.73; H, 4.33; N, 3.34 Found (%): C, 68.66; H, 4.37; N, 3.47
EXAMPLE 9
3,4-trans-4-(4-Fluorophenyl)-1,2,3,4-tetrahydro-2-methyl-N-(3-methylphenyl)
-1-oxo-3-isoquinolinecarboxamide (A)
Melting point: 273.degree.-275.degree. C. (recrystallized from chloroform)
NMR (200 MHz, DMSO-d.sub.6) ppm: 2.25 (3H,s), 2.88 (3H,s), 4.54 (1H,s),
4.65 (1H,s), 6.83-7.43 (11H,m), 7.96-8.00 (1H,m)
Elemental analysis (for C.sub.24 H.sub.21 N.sub.2 O.sub.2 F): Calculated
(%): C, 74.21; H, 5.45; N, 7.21 Found (%): C, 73.75; H, 5.20; N, 7.32
EXAMPLE 10
3,4-trans-4-(2-Chlorophenyl)-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1,6,
7-trimethyl-2-oxo-3-quinolinecarboxamide (A)
Melting point: 230.degree.-233.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.19 (3H,s), 2.29
(3H,s), 3.44 (3H,s), 4.00 (1H, d,J=1.6 Hz), 5.30 (1H,s like), 6.57-6.65
(1H,m), 6.72-6.90 (2H,m), 6.89 (1H,s), 7.00-7.23 (2H,m), 7.01 (1H,s),
7.37-7.45 (1H,m), 8.11-8.26 (1H,m), 8.43 (1H,bs)
Elemental analysis (for C.sub.25 H.sub.21 N.sub.2 O.sub.2 ClF.sub.2):
Calculated (%): C, 66.01; H, 4.65; N, 6.16 Found (%): C, 65.98; H, 4.85;
N, 6.03
EXAMPLE 11
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-me
thyl-2-oxo-4-phenyl-3-quinolinecarboxamide (A)
Melting point: 201.degree.-203.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.98 (6H,d,J=6.2
Hz), 1.08 (6H,d,J=6.6 Hz), 2.68 (2H,m), 3.45 (3H,s), 4.02 (1H,d,J=4.0 Hz),
4.49 (1H,d,J=3.6 Hz), 6.90-7.50 (12H,m)
Elemental analysis (for C.sub.29 H.sub.31 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 73.33; H, 6.58; N, 5.90 Found (%): C, 73.06; H, 6.61; N,.5.92
EXAMPLE 12
3,4-cis-4-›3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl!-N-›2,6-bis(1-methyle
thyl)phenyl!-1,2,3,4-tetrahydro-2-methyl-1-oxo-3-isoquinolinecarboxamide
A mixture of the compound obtained in Example 6 (300 mg), acetic acid (8
ml) and 10% palladium-carbon (50% hydrated) (150 mg) was stirred at
90.degree. to 100.degree. C. in a hydrogen atmosphere for 15 hours. After
cooling, the mixture was filtered, the filtrate being distilled to remove
the solvent. The residue was dissolved in ethyl acetate and washed
successively with water, aqueous sodium hydrogen carbonate and water and
then dried, after which the solvent was distilled off, to yield the title
compound as colorless crystals (160 mg).
Melting point: 268.degree.-270.degree. C. (recrystallized from
acetone-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.87 (6H,d,J=6.8 Hz),
1.00 (6H,d,J=6.8 Hz), 1.39 (18H,s), 2.41 (1H,m), 3.41 (3H,s), 4.40
(1H,d,J=5.6 Hz), 4.93 (1H,d, J=5.6 Hz), 5.22 (1H,s), 6.82 (1H,s),
7.02-7.53 (8H,m), 8.16-8.20 (1H,m)
Elemental analysis (for C.sub.37 H.sub.48 N.sub.2 O.sub.3): Calculated (%):
C, 78.13; H, 8.51; N, 4.92 Found (%): C, 77.94; H, 8.60; N, 4.83
EXAMPLE 13
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-4-(4-fluorophenyl)-3,4-dihydro-6
-(1-methylethyl)-2-oxo-2H-1-benzopyran-3-carboxamide
The compound obtained in Example 4 was reacted in substantially the same
manner as in Example 12 to yield the title compound as colorless crystals.
Melting point: 223.degree.-225.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.98, 1.06 (each
6H,d,J=7.0 Hz), 1.16, 1.17 (each 3H,d,J=7.0 Hz), 2.65 (2H,b), 2.82 (1H,m),
3.98 (1H,d,J=7.0 Hz), 5.00 (1H,d,J=7.0 Hz), 6.86-7.29 (10H,m)
Elemental analysis (for C.sub.31 H.sub.34 NO.sub.3 F): Calculated (%): C,
76.36; H, 7.03; N, 2.87 Found (%): C, 76.06; H, 7.14; N, 3.08
EXAMPLE 14
N-(2,5-Dimethoxyphenyl)-4-(4-fluorophenyl)-3,4-dihydro-1-oxo-1H-2-benzopyra
n-3-carboxamide
The compound obtained in Example 8 was reacted in substantially the same
manner as in Example 12 to yield the title compound as colorless crystals.
Melting point: 133.degree.-136.degree. C. (recrystallized from
acetone-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.72 (3H,s), 3.78
(3H,s), 4.83 (1H,d,J=3.5 Hz), 5.35 (1H,d,J=3.5 Hz), 6.57 (1H,dd,J=12.0,
2.8 Hz), 6.73 (1H,d,J=9.0 Hz), 6.83-7.07 (4H,m), 7.31 (1H,d,J=7.2 Hz),
7.50-7.70(2H,m), 7.86 (1H, d, J=2.6 Hz), 8.25 (1H,d,J=7.6 Hz), 8.49 (1H,b)
Elemental analysis (for C.sub.24 H.sub.20 NO.sub.5 F.cndot.1/3H.sub.2 O):
Calculated (%): C, 67.94; H, 4.91; N, 3.30 Found (%): C, 67.73; H, 4.98;
N, 3.30
EXAMPLE 15
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-1,2,3,4-tetra
hydro-1,6,7-trimethyl-3-quinolinecarboxamide (A)
Melting point: 145.degree.-146.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.06 (12H,d like, J=6.6 Hz),
2.07 (3H,s), 2.24 (3H,s), 2.71 (2H,m), 3.01 (3H,s), 3.11 (1H,m), 3.25-3.52
(2H,m), 4.90 (1H,d, J=3.2 Hz), 6.62 (2H,s), 6.80-6.90 (1H,m), 7.05-7.30
(5H,m), 7.40-7.50 (1H,m), 7.56 (1H,bs)
Elemental analysis (for C.sub.31 H.sub.37 N.sub.2 OCl): Calculated (%): C,
76.13; H, 7.62; N, 5.73 Found (%): C, 75.95; H, 7.74; N, 5.80
EXAMPLE 16
N-›2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl
-3-quinolineacetamide (trans:cis=about 3:1 mixture) (A)
Melting point: 214.degree.-216.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.90-1.30, 1.17
(total 12H,m,d,J=7.0 Hz), 2.06, 2.35-3.05 (total 2H,d,J=5.8 Hz, m),
2.90-3.20 (2H,m), 3.35-3.70 (1H,m), 3.38, 3.46, 3.51 (total 3H, each s),
4.30, 4.33, 4.41 (1H, each d,J=6.2 Hz, J=11.0 Hz, J=8.0 Hz), 6.55-7.60
(13H,m)
Elemental analysis (for C.sub.30 H.sub.34 N.sub.2 O.sub.2): Calculated (%):
C, 79.26; H, 7.54; N, 6.16 Found (%): C, 79.10; H, 7.65; N, 6.30
EXAMPLE 17
4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-N-(3-methylphenyl)-2-oxo-3-q
uinolineacetamide (trans:cis=about 3:1 mixture) (A)
Melting point: 161.degree.-162.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.25-2.55 (1H,m),
2.31 (3H,s), 2.60-2.80 (1H,m), 3.40-3.65 (0.75H,m), 3.47 (2.25H,s), 3.50
(0.75H,s), 3.70-3.85 (0.25H,m), 4.76 (0.75H,d,J=13 Hz), 5.05
(0.25H,d,J=7.0 Hz), 6.63 (0.75H,d,J=7.8 Hz), 6.85-7.50 (11.25H,m), 7.85
(0.25H,bs), 8.11 (0.75H,bs)
Elemental analysis (for C.sub.25 H.sub.23 N.sub.2 O.sub.2
Cl.cndot.0.2H.sub.2 O): Calculated (%): C, 71.07; H, 5.58; N, 6.63 Found
(%): C, 71.07; H, 5.56; N, 6.53
EXAMPLE 18
N-›2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methyl-
2-oxo-4-phenyl-3-quinolineacetamide (trans:cis=about 4:1 mixture) (A)
Melting point: 205.degree.-207.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.85-1.35, 1.17
(total 12H,m,d, J=6.8 Hz), 2.04, 2.55-2.80 (total 2H,d,J=5.2 Hz, m), 3.06
(2H,m), 3.30-3.55 (1H,m), 3.36, 3.42, 3.45 (total 3H, each s), 3.62, 3.65
(total 3H, each s), 3.89, 3.90, 3.94 (total 3H, each s), 4.24, 4.33 (total
1H, each d, J=10 Hz, J=11Hz), 6.21, 6.30 (total 1H, each s), 6.56, 6.66
(total 1H, each s), 7.00-7.50 (9H,m)
Elemental analysis (for C.sub.32 H.sub.38 N.sub.2 O.sub.4): Calculated (%):
C, 74.68; H, 7.44; N, 5.44 Found (%): C, 74.82; H, 7.50; N, 5.86
EXAMPLE 19
N-›2,6-Bis-(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-
2-oxo-4-phenyl-3-quinolineacetamide (A)
Melting point: 236.degree.-237.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.13 (12H,d,J=6.6
Hz), 1.49 (3H,s), 2.01 (1H, dd,J=14.4 Hz, J=2.0 Hz), 2.88 (1H,dd,J=14.4
Hz, J=9.6 Hz), 3.00 (2H,m), 3.40, 3.45 (total 3H, each s), 3.86
(1H,d,J=9.8 Hz), 6.53 (1H,d,J=2.4 Hz), 6.9-7.5 (10H,m)
Elemental analysis (for C.sub.31 H.sub.35 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 74.01; H, 7.01; N, 5.57 Found (%): C, 73.71; H, 6.89; N, 5.87
EXAMPLE 20
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-4-(2-chlorophenyl)-1,2,3,4-tetra
hydro-1,6,7-trimethyl-2-oxo-3-quinolineacetamide (A)
Melting point: 213.degree.-215.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.95-1.30, 1.16
(total 12H,m,d,J=6.8 Hz), 2.06, 2.13 (total 3H, each s), 2.24, 2.30 (total
3H, each s), 2.56 (1H,dd,J=15.0, 3.8 Hz), 2.79 (1H,dd,J=15.0, 7.8 Hz),
3.06 (2H,m), 3.39, 3.45 (total 3H, each s), 3.40-3.60 (1H,m), 4.69, 4.85
(total 1H, each d, J=10.0 Hz, J=13.0 Hz), 6.23, 6.47 (total 1H, each s),
6.79, 6.90 (total 1H, each s), 7.00-7.30, 7.40-7.55, 7.55 (total 8H,m,m,s)
Elemental analysis (for C.sub.32 H.sub.37 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 74.33; H, 7.21; N, 5.42 Found (%): C, 74.13; H, 7.09; N, 5.83
EXAMPLE 21
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-chlorophenyl)-1,2,
3,4-tetrahydro-1-methyl-2-oxo-3-quinolineacetamide (A)
Melting point: 231.degree.-234.degree. C. (recrystallized from ethyl
acetate-isopropyl ether-ethanol) NMR (200 MHz, CDCl.sub.3) ppm: 1.00-1.30,
1.16 (total 12H,m,d,J=6.8 Hz), 2.55 (1H,dd,J=15.0, 4.0 Hz), 2.76
(1H,dd,J=15.0, 7.4 Hz), 3.06 (2H,m), 3.39, 3.45 (total 3H, each s),
3.40-3.70 (1H,m), 4.83, 4.96 (total 1H, each d, J=12.0 Hz, J=14.0 Hz),
6.46, 6.62 (total 1H, each s), 6.90-7.56 (10H,m)
Elemental analysis (for C.sub.30 H.sub.32 N.sub.2 O.sub.2 Cl.sub.2
.cndot.0.2CH.sub.3 CO.sub.2 C.sub.2 H.sub.5): Calculated (%): C, 68.37; H,
6.26; N, 5.18 Found (%): C, 68.14; H, 6.42; N, 5.24
EXAMPLE 22
3,4-cis-6-Chloro-1,2,3,4- tetrahydro
-1-methyl-N-›2-methyl-6-(1-methylethyl)phenyl!-2-oxo-4-phenyl-3-quinolinea
cetamide
To a solution of
6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetic acid
(trans:cis=about 4:1 mixture, described in Reference Example 12) (220 mg)
in anhydrous THF (7 ml) were added oxalyl chloride (0.11 ml) and DMF (one
drop) at room temperature, followed by stirring for 0.5 hours. After the
solvent was distilled off, the residue was dissolved in anhydrous THF (10
ml). To this solution was added a solution of 2-isopropyl-6-methylaniline
(0.135 ml) and triethylamine (0.11 ml) in anhydrous THF (5 ml), followed
by stirring at room temperature for 0.5 hours. After the solvent was
distilled off, ethyl acetate was added to the residue, which was then
washed successively with water, dilute hydrochloric acid, water, aqueous
sodium hydrogen carbonate and water and then dried, followed by
concentration, to yield the compound of Example 23 as colorless crystals
(120 mg). After the filtrate was distilled to remove the solvent, the
residue was subjected to silica gel column chromatography (eluted with
hexane:ethyl acetate=1:0.fwdarw.3:1); the title compound, as colorless
crystals (35 mg), was obtained in the first fraction, the compound of
Example 23 described below, as additional colorless crystals (25 mg), was
obtained in the second fraction.
Melting point: 162.degree.-164.degree. C. (recrystallized from isopropyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.17 (3H,d,J=7.2 Hz), 1.20
(3H,d,J=7.2 Hz), 2.23 (3H,s), 2.37 (1H,dd,J=15.1, 4.8 Hz), 2.91
(1H,dd,J=15.1, 7.8 Hz), 3.09
(1H,m),3.48(3H,s),3.65(1H,m),4.25(1H,d,J=6.7Hz),7.01-7.37(11H,m)
Elemental analysis (for C.sub.28 H.sub.29 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 72.95; H, 6.34; N, 6.08 Found (%): C, 72.64; H, 6.57; N, 6.19
EXAMPLE 23
3,4-trans-6-Chloro-1-methyl-N-›2-methyl-6-(1-methylethyl)phenyl!-2-oxo-4-ph
enyl-1,2,3,4-tetrahydro-3-quinolineacetamide
The title compound, along with the compound of Example 22, was obtained as
colorless crystals by the method described in Example 22.
Melting point: 238.degree.-240.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3 +DMSO-d.sub.6) ppm: 1.16
(3H,d,J=7.0 Hz), 1.17 (3H, d,J=7.0 Hz), 2.21 (3H,s), 2.57-2.64 (2H,m),
3.10 (1H,m), 3.39 (3H,s), 3.34-3.50 (1H,m), 4.35 (1H,d, J=8.8 Hz), 6.79
(1H,d,J=2.4 Hz), 7.01-7.40 (10H, m), 8.48 (1H,s)
Elemental analysis (for C.sub.28 H.sub.29 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 72.95; H, 6.34; N, 6.08 Found (%): C, 72.64; H, 6.40; N, 6.15
The compounds of Examples 24 through 33 were obtained in the same reaction
as in Example 22, using the carboxylic acid used in Example 22 and
respective corresponding anilines.
EXAMPLE 24
3,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimet
hoxyphenyl)-3-quinolineacetamide
Melting point: 160.degree.-162.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.20 (1H,dd,J=14.4
Hz, J=2.0 Hz), 3.10 (1H, dd,J=14.4 Hz, J=9.6 Hz), 3.39, 3.46 (total 3H,
each s), 3.81 (3H,s), 3.84 (6H, s), 4.34 (1H,d,J=7.0 Hz), 6.17 (2H,s),
6.65 (1H, s), 6.9-7.3 (7H,m)
Elemental analysis (for C.sub.27 H.sub.27 N.sub.2 O.sub.5 Cl): Calculated
(%): C, 65.52; H, 5.50; N, 5.66 Found (%): C, 65.51; H, 5.84; N, 5.84
EXAMPLE 25
3,4-trans-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trim
ethoxyphenyI)-3-quinolineacetamide
Melting point: 157.degree.-158.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.58 (1H,d,J=6.2
Hz), 3.32, 3.40 (total 3H, each s), 3.66, 3.79 (total 9H, each s), 4.37
(1H,d,J=7.6 Hz), 6.14 (2H,s), 6.85 (1H,d,J=2.4 Hz), 6.7-7.4 (7H,m)
Elemental analysis (for C.sub.27 H.sub.27 N.sub.2 O.sub.5 Cl): Calculated
(%): C, 65.52; H, 5.50; N, 5.66 Found (%): C, 65.47; H, 5.60; N, 5.74
EXAMPLE 26
3,4-cis-6-Chloro-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4
-phenyl-3-quinolineacetamide
Melting point: 198.degree.-200.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.34 (1H,dd,J=15.0
Hz, J=4.8 Hz), 2.81 (1H, dd,J=15.0 Hz, J=4.0 Hz), 3.47 (3H,s), 3.61
(1H,m), 4.19 (1H,d,J=6.6 Hz), 6.8-7.3 (9H,m), 7.96 (1H,bs), 8.21 (1H,m)
Elemental analysis (for C.sub.24 H.sub.19 N.sub.2 O.sub.2 ClF.sub.2):
Calculated (%): C, 65.38; H, 4.34; N, 6.35 Found (%): C, 65.32; H, 4.41;
N, 6.37
EXAMPLE 27
3,4-trans-6-Chloro-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo
-4-phenyl-3-quinolineacetamide
Melting point: 165.degree.-168.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.55 (1H,m), 3.43
(3H,s), 3.43 (1H,m), 4.18 (1H,d,J=13.2 Hz), 6.60 (1H,m), 6.86 (2H,m), 6.97
(1H,d,J=8.6 Hz), 7.2-7.5 (7H,m), 7.8 (1H,bs), 8.2 (1H,m)
Elemental analysis (for C.sub.24 H.sub.19 N.sub.2 O.sub.2 ClF2): Calculated
(%): C, 65.38; H, 4.34; N, 6.35 Found (%): C, 65.51; H, 4.34; N, 6.36
EXAMPLE 28
3,4-cis-6-Chloro-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4
-phenyl-3-quinolineacetamide
Melting point: 203.degree.-205.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.30 (6H,s), 2.37
(1H,dd,J=15.2 Hz, J=4.8 Hz), 2.87 (1H,dd,J=15.0 Hz, J=8.2 Hz), 3.47
(3H,s), 3.64 (1H,m), 4.24 (1H, d,J=6.6 Hz), 7.0-7.4 (1H,m)
Elemental analysis (for C.sub.26 H.sub.25 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 72.13; H, 5.82; N, 6.47 Found (%): C, 71.75; H, 5.84; N, 6.55
EXAMPLE 29
3,4-trans-6-Chloro-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo
-4-phenyl-3-quinolineacetamide
Melting point: 201.degree.-203.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.20 (6H,s), 2.59
(2H,m), 3.38 (1H,m), 3.43 (3H,s), 4.29 (1H,d,J=12.0 Hz), 6.64 (1H,m),
6.9-7.4 (10H,m)
Elemental analysis (for C.sub.26 H.sub.25 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 72.13; H, 5.82; N, 6.47 Found (%): C, 71.57; H, 5.76; N, 6.65
EXAMPLE 30
3,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimet
hylphenyl)-3-quinolineacetamide
Melting point: 224.degree.-227.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.19 (6H,s), 2.25
(3H,s), 2.35 (1H,dd,J=15.2 Hz,J=4.8 Hz), 2.86 (1H,dd,J=15.4 Hz, J=7.8 Hz),
3.47 (3H,s), 3.63 (1H,m), 4.24 (1H,d,J=6.6 Hz), 6.88 (1H,s), 7.0-7.3
(9H,m)
Elemental analysis (for C.sub.27 H.sub.27 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 72.55; H, 6.09; N, 6.27 Found (%): C, 72.33; H, 6.27; N, 6.44
EXAMPLE 31
3,4-trans-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trim
ethylphenyl)-3-quinolineacetamide
Melting point: 191.degree.-193.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.16 (6H,s), 2.24
(3H,s), 2.58 (2H,m), 3.4 (1H,m), 3.42 (3H,s), 4.29 (1H,d,J=11.8 Hz), 6.65
(1H,m), 6.86 (2H,s), 6.98 (1H,d, J=8.6 Hz), 7.1-7.5 (6H,m)
Elemental analysis (for C.sub.27 H.sub.27 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 72.55; H, 6.09; N, 6.27 Found (%): C, 72.64; H, 6.11; N, 6.36
EXAMPLE 32
3,4-cis-N-›2,6-Bis(1-methylethyl)phenyI!-6-chloro-1,2,3,4-tetrahydro-1-meth
yl-2-oxo-4-phenyl-3-quinolineacetamide
Melting point: 208.degree.-210.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.18 (12H, t like,
J=6.8 Hz), 2.37 (1H, dd, J=15.0, 5.4 Hz), 2.96 (1H,dd,J=15.0, 7.6 Hz),
3.08 (2H,m), 3.48 (3H,s), 3.55-3.70 (1H,m), 4.27 (1H,d,J=6.6 Hz),
7.00-7.35 (12H,m)
Elemental analysis (for C.sub.30 H.sub.33 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 73.68; H, 6.80; N, 5.73 Found (%): C, 73.75; H, 6.86; N, 5.68
EXAMPLE 33
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-me
thyl-2-oxo-4-phenyl-3-quinolineacetamide
Melting point: 259.degree.-260.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, DMSO-d.sub.6) ppm: 1.11
(12H,d,J=7.0 Hz), 1.83 (1H,dd, J=15.0, 9.0 Hz), 2.37 (1H,dd,J=15.0, 5.2
Hz), 2.67 (1H,m), 2.90-3.20 (2H,m), 2.96 (3H,s), 3.32 (3H,s), 4.19
(1H,d,J=4.8 Hz), 6.68-6.82 (2H,m), 7.00-7.40 (9H,m), 9.17 (1H,s)
Elemental analysis (for C.sub.30 H.sub.33 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 73.68; H, 6.80; N, 5.73 Found (%): C, 73.72; H, 6.92; N, 5.63
EXAMPLE 34
3,4-cis-N-›2,6-Bis-(1-methylethyl)phenyl!-6-chloro-3,4-dihydro-2-oxo-4-phen
yl-2H-1-benzopyran-3-acetamide (A)
Melting point: 229.degree.-232.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.18 (12H,d,J=7.0
Hz), 2.42 (1H,dd,J=15.8 Hz, J=6.2 Hz), 2.85 (1H,dd,J=16.0 Hz, J=7.0 Hz),
3.08 (2H,m), 3.84 (1H,m), 4.39 (1H,d,J=7.0 Hz), 6.5 (1H,bs)7.1-7.4 (10H,m)
Elemental analysis (for C.sub.29 H.sub.30 NO.sub.3 Cl): Calculated (%): C,
73.17; H, 6.35; N, 2.94 Found (%): C, 73.06; H, 6.48; N, 2.97
EXAMPLE 35
3,4-trans-N-›2,6-Bis-(1-methylethyl)phenyl!-3,4-dihydro-6-methyl-2-oxo-4-ph
enyl-2H-1-benzopyran-3-acetamide (A)
Melting point: 245.degree.-247.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.17 (12H,d,J=6.8
Hz), 2.17, 2.21 (total 3H, each s), 2.63 (1H,m), 3.06 (2H,m), 3.58 (2H,m),
4.44 (1H,d,J=11.2 Hz), 6.49 (1H,bs), 6.78 (1H,bs), 7.0-7.5 (6H,m)
Elemental analysis (for C.sub.30 H.sub.33 NO.sub.3): Calculated (%): C,
79.09; H, 7.30; N, 3.07 Found (%): C, 79.06; H, 7.39; N, 3.07
EXAMPLE 36
3,4-cis-N-
›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-methyl-4-phen
yl-3-quinolineacetsmide(B)
Melting point: 239.degree.-241.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, DMSO-d.sub.6)ppm: 1.11 (12H,d,J=6.6
Hz), 2.25-2.35 (2H,m), 3.02 (2H,m), 3.20-3.40 (3H,m), 3.32 (3H,s), 4.30
(1H,d,J=6.6 Hz), 6.88 (1H, d,J=2.2 Hz), 7.00-7.50 (10H,m), 9.20 (1H,s)
Elemental analysis (for C.sub.30 H.sub.35 N.sub.2 OCl): Calculated (%): C,
75.85; H, 7.43; N, 5.90 Found (%): C, 76.17; H, 7.52; N, 5.77
EXAMPLE 37
3,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-4-phenyl-N-(2,4,6-trimethoxyph
enyl)-3-quinolineacetamide (B)
Melting point: 179.degree.-180.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.96 (1H,dd,J=15,
8.2 Hz), 2.21 (1H,dd, J=15, 6.2 Hz), 2.86 (1H,m), 2.99 (3H,s), 3.15-3.30
(2H,m), 3.81 (9H,s), 4.21 (1H,d,J=4.6 Hz), 6.15 (2H,s), 6.34 (1H,s), 6.58
(1H,d,J=8.8 Hz), 6.84 (1H,s like), 7.00-7.35 (6H,m)
Elemental analysis (for C.sub.27 H.sub.29 N.sub.2 O.sub.4 Cl): Calculated
(%): C, 67.42; H, 6.08; N, 5.82 Found (%): C, 67.36; H, 6.20; N, 5.67
EXAMPLE 38
3,4-cis-6-Chloro-N-(2,4-difluorophenyl)-1,2,3,4-tetrahydro-1-methyl-4-pheny
l-3-quinolineacetamide (B)
Melting point: 161.degree.-162.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.99 (1H,dd,J=15,
8.2 Hz), 2.24 (1H,dd, J=15, 6.4 Hz), 2.88 (1H,m), 2.97 (3H,s), 3.15-3.25
(2H,m), 4.21 (1H,d, J=4.8 Hz), 6.61 (1H,d,J=8.8 Hz), 6.80-7.35 (10H,m),
8.15-8.30 (1H,m)
Elemental analysis (for C.sub.24 H.sub.21 N.sub.2 OClF.sub.2
.cndot.0.2CH.sub.3 CO.sub.2 C.sub.2 H.sub.5): Calculated (%): C, 67.01; H,
5.12; N, 6.30 Found (%): C, 66.71; H, 4.96; N, 6.61
EXAMPLE 39
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1-oxo-4-pheny
l-2,6,7-trimethyl-3-isoquinolineacetamide (A)
Melting point: 280.degree.-282.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.00-1.35, 1.23
(total 12H,m,d,J=7.0 Hz), 2.22, 2.24, 2.28, 2.33 (total 6H, each s), 2.58
(1H,dd,J=15.0, 10.0 Hz), 2.75, 2.96 (total 3H, each s), 2.89 (1H,dd,
J=15.0, 4.6 Hz), 3.08 (2H,m), 4.05-4.35 (1H,m), 4.21, 4.23 (total 1H, each
s), 6.85-7.40 (10H,m), 7.76, 7.94 (total 1H, each s)
Elemental analysis (for C.sub.32 H.sub.38 N.sub.2 O.sub.2): Calculated (%):
C, 79.63; H, 7.94; N, 5.80 Found (%): C, 79.56; H, 8.03; N, 5.74
EXAMPLE 40
3,4-trans-1,2,3,4-Tetrahydro-1-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-2,6,
7-trimethyl-3-isoquinolineacetamide (A)
Melting point: 213.degree.-214.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.23, 2.27, 2.34
(total 6H, each s), 2.50 (1H,dd, J=14.0, 10.0 Hz), 2.78 (1H,dd,J=14.0, 4.8
Hz), 2.79, 2.98 (total 3H, each s), 3.67, 3.82 (total 9H, each s),
3.90-4.30 (1H,m), 4.23, 4.33 (total 1H,s,),6.02, 6.17 (total 2H, each s),
6.32, 6.41 (total 1H, each s), 6.85-7.30 (6H,m), 7.80, 7.96 (total 1H,
each s)
Elemental analysis (for C.sub.29 H.sub.32 N.sub.2 O.sub.5): Calculated (%):
C, 71.29; H, 6.60; N, 5.73 Found (%): C, 71.19; H, 6.62; N, 5.68
EXAMPLE 41
3,4-trans-N-(2,4-Difluorophenyl)-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4
-phenyl-3-isoquinolineacetamide (A)
Melting point: 176.degree.-177.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.26 (3H,s), 2.32
(3H,s), 2.61 (1H,dd,J=15.0, 8.8 Hz), 2.77 (1H,dd,J=15.0, 5.0 Hz), 2.94
(3H,s), 4.15-4.30 (1H,m), 4.17 (1H,s), 6.80-7.30 (8H,m), 7.41 (1H,bs),
7.92 (1H,s), 8.10-8.30 (1H,m)
Elemental analysis (for C.sub.26 H.sub.24 N.sub.2 O.sub.2 F.sub.2):
Calculated (%): C, 71.87; H, 5.57; N, 6.45 Found (%): C, 71.63; H, 5.68;
N, 6.24
EXAMPLE 42
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo
-4-phenyl-3-quinoxalineacetamide (A)
Melting point: 205.degree.-206.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.09 (6H,d,J=6.8 Hz), 1.16
(6H,d,J=7.0 Hz), 2.63 (1H,dd,J=15.0, 8.6 Hz), 2.84 (1H,dd,J=15.0, 4.6 Hz),
3.02 (2H,m), 3.44 (3H,s), 5.15 (1H,dd,J=8.6, 4.6 Hz), 6.90-7.35 (12H,m)
Elemental analysis (for C.sub.29 H.sub.32 N.sub.3 O.sub.2 Cl): Calculated
(%): C, 71.08; H, 6.58; N, 8.57 Found (%): C, 71.29; H, 6.61; N, 8.81
EXAMPLE 43
6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphen
yl)-3-quinoxalineacetamide (A)
Melting point: 236.degree.-238.degree. C. (recrystallized from
THF-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.51 (1H,dd,J=14.0,
9.6 Hz), 2.73 (1H,dd, J=14.0, 3.8 Hz), 3.43 (3H, s), 3.65 (6H,s), 3.79
(3H,s), 5.10 (1H,dd,J=9.6, 3.8 Hz), 6.11 (2H,s), 6.57 (1H,s), 6.90-7.35
(8H,m)
Elemental analysis (for C.sub.26 H.sub.26 N.sub.3 O.sub.5 Cl): Calculated
(%): C, 62.97; H, 5.28; N, 8.47 Found (%): C, 62.61; H, 5.48; N, 8.20
EXAMPLE 44
6-Chloro-N-(2,4-difiuorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-
3-quinoxalineacetamide (A)
Melting point: 160.degree.-161.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.68 (1H,dd,J=15.0, 7.0 Hz),
2.80 (1H,dd, J=15.0, 5.8 Hz), 3.45 (3H,s), 4.99 (1H,t like, J=6.3 Hz),
6.78-7.42 (10H,m), 7.76 (1H,m), 8.10-8.30 (1H,m)
Elemental analysis (for C.sub.23 H.sub.18 N.sub.3 O.sub.2 ClF.sub.2):
Calculated (%): C, 62.52; H, 4.11; N, 9.51 Found (%): C, 62.57; H, 4.23;
N, 9.74
EXAMPLE 45
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phen
yl-3-quinolineacetamide
To a solution of the compound obtained in Reference Example 18 (100 ml) in
1,2-dichloroethane (5 ml) were added 1-hydroxybenzotriazole (45 mg) and
1,3-dicyclohexylcarbodiimide (90 mg), followed by stirring at room
temperature for 0.5 hours. To this mixture was added
2,6-diisopropylaniline (0.5 ml), followed by heating under reflux for 10
hours. After the reaction mixture was concentrated, ethyl acetate was
added to the residue, the precipitated crystals were separated by
filtration. The filtrate was washed successively with hydrochloric acid,
water, aqueous potassium carbonate and water and then dried, after which
the solvent was distilled off, to yield the title compound as colorless
crystals (105 mg).
Melting point: 237.degree.-238.degree. C. (recrystallized from
acetone-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.09 (12H,d,J=6.8 Hz),
2.98 (1H,m), 3.62 (2H,s), 3.88 (3H,s), 7.09-7.60 (11H,m), 8.53 (1H,s)
Elemental analysis (for C.sub.30 H.sub.31 N.sub.2 O.sub.2 Cl): Calculated
(%): C, 73.98; H, 6.42; N, 5.75 Found (%): C, 73.75; H, 6.64; N, 5.72
EXAMPLE 46
6-Chloro-N-(2,4-difluorophenyl)-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quino
lineacetamide (B)
Melting point: 217.degree.-218.degree. C. (recrystallized from
acetone-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.54 (2H,s), 3.87
(3H,s), 6.77-6.87 (2H,m), 7.15 (1H,d,J=2.4 Hz), 7.29-7.58 (9H,m), 8.19
(1H,m), 9.28 (1H,b)
Elemental analysis (for C.sub.24 H.sub.17 N.sub.2 O.sub.2 ClF.sub.2):
Calculated (%): C, 65.68; H, 3.90; N, 6.38 Found (%): C, 65.81; H, 4.16;
N, 6.44
EXAMPLE 47
N-›2,6-Bis(1-methylethyl)phenyl!-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl
-3-isoquinolineacetamide (A)
Melting point: 265.degree.-270.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.00-1.30, 1.12
(total 12H,m,d,J=6.8 Hz), 2.18, 2.24 (total 3H, each s), 2.34, 2.38 (total
3H, each s), 2.83 (2H,m), 3.03, 3.14 (total 2H, each s), 3.77, 3.78 (total
3H, each s), 6.55-6.80 (2H,m), 7.10-7.60 (8H,m), 8.15-8.30 (1H,m)
Elemental analysis (for C.sub.32 H.sub.36 N.sub.2 O.sub.2
.cndot.0.25CH.sub.3 CO.sub.2 C.sub.2 H.sub.5): Calculated (%): C, 78.85;
H, 7.62; N, 5.57 Found (%): C, 78.82; H, 7.37; N, 5.56
EXAMPLE 48
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1-oxo-4-phenyI-1H-2-benzopyran-3-
acetamide (B)
Melting point: 183.degree.-184.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.16 (12, d,J=6.8 Hz),
3.03 (2H,m), 3.54 (2H,s), 6.94-7.55 (11H,m), 8.31 (1H,d,J=8.6 Hz)
Elemental analysis (for C.sub.29 H.sub.28 NO.sub.3 Cl): Calculated (%): C,
73.49; H, 5.95; N, 2.96 Found (%): C, 73.37; H, 6.15; N, 2.89
EXAMPLE 49
6-Chloro-N-(2,4-difluorophenyl)-1-oxo-4-phenyl-1H-2-benzopyran-3-acetamide
(B)
Melting point: 244.degree.-245.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.50 (2H,s), 6.81-6.90
(2H,m), 7.01 (1H,d, J=1.6 Hz), 7.34-7.54 (6H,m), 8.25 (1H,m), 8.28
(1H,d,J=8.4 Hz)
Elemental analysis (for C.sub.23 H.sub.14 NO.sub.3 ClF.sub.2): Calculated
(%): C, 64.88; H, 3.31; N, 3.29 Found (%): C, 64.82; H, 3.49; N, 3.26
EXAMPLE 50
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-
acetamide (A)
Melting point: 252.degree.-255.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.15 (12H,d,J=7.0
Hz), 3.03 (2H,m), 3.52 (2H,s), 7.0-7.6 (11H,m)
Elemental analysis (for C.sub.29 H.sub.28 NO.sub.3 Cl): Calculated (%): C,
73.49; H, 5.95; N, 2.96 Found (%): C, 73.36; H, 5.85; N, 3.26
EXAMPLE 51
6-Chloro-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-1-benzopyran-3-acetam
ide (A)
Melting point: 257.degree.-259.degree. C. (recrystallized from
chloroform-ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm:
3.49 (2H,s), 3.79 (9H,s), 6.12 (2H,s), 7.0-7.6 (9H,m)
Elemental analysis (for C.sub.26 H.sub.22 NO.sub.6 Cl): Calculated (%): C,
65.07; H, 4.62; N, 2.92 Found (%): C, 64.81; H, 4.44; N, 3.02
EXAMPLE 52
6-Chloro-N-(2,4-difiuorophenyl)-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide
(A)
Melting point: 225.degree.-227.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.49 (2H,s),
6.8-6.9 (2H,m), 7.05 (1H,d, J=2.4 Hz), 7.3-7.6 (6H,m), 8.1-8.3 (2H,m)
Elemental analysis (for C.sub.23 H.sub.14 NO.sub.3 ClF.sub.2): Calculated
(%): C, 64.88; H, 3.31; N, 3.29 Found (%): C, 64.26; H, 3.54; N, 3.00
EXAMPLE 53
N-›2,6-Bis(1-methylethyl)phenyl!-6-methyl-2-oxo-4-phenyl-2H-1-35-benzopyran
-3-acetamide (A)
Melting point: 257.degree.-258.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.14 (12H,d,J=7.0
Hz), 2.29 (3H,s), 2.03 (2H,m), 3.51 (2H,s), 6.85 (1H,s), 7.1-7.7 (10H,m)
Elemental analysis (for C.sub.30 H.sub.31 NO.sub.3): Calculated (%): C,
79.44; H, 6.89; N, 3.09 Found (%): C, 79.15; H, 6.75; N, 3.14
EXAMPLE 54
6-Methyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-1-benzopyran-3-acetam
ide (A)
Melting point: 256.degree.-257.degree. C. (recrystallized from
chloroform-ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm:
2.27 (3H,s), 3.47 (2H,s), 3.76 (3H,s), 3.78 (6H,s), 6.11 (2H,s), 6.83
(1H,s), 7.2-7.6 (7H,m)
Elemental analysis (for C.sub.27 H.sub.25 NO.sub.6): Calculated (%): C,
70.58; H, 5.48; N, 3.05 Found (%): C, 70.22; H, 5.60; N, 2.95
EXAMPLE 55
N-(2,4-Difluorophenyl)-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide
(A)
Melting point: 168.degree.-170.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.28 (3H,s), 3.47
(2H,s), 6.8-6.9 (3H,m), 7.3-7.5 (4H,m), 7.5-7.6 (3H,m), 8.1-8.3 (1H,m),
8.45 (1H,bs)
Elemental analysis (for C.sub.24 H.sub.17 NO.sub.3 F.sub.2): Calculated
(%): C, 71.11; H, 4.23; N, 3.46 Found (%): C, 70.84; H, 4.25; N, 3.54
EXAMPLE 56
N-›2,6-Bis(1-methylethyI)phenyl!-4-(2-methoxyphenyl)-1-oxo-1H-2-benzopyran-
3-acetamide (B)
Melting point: 250.degree.-252.degree. C. (recrystallized from
acetone-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.08, 1.15 (total 12H,
each d, J=6.6 Hz), 2.96 (2H,m), 3.47 (1H,d,J=15.4 Hz), 3.60 (1H,d,J=15.4
Hz), 3.62 (3H,s), 6.91-7.67 (10H,m), 8.38 (1H,dd,J=7.8, 1.7 Hz)
Elemental analysis (for C.sub.30 H.sub.31 NO.sub.4): Calculated (%): C,
76.73; H, 6.65; N, 2.98 Found (%): (D, 76.58; H, 6.79; N, 3.00
EXAMPLE 57
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-phenyl-3-quinolineacetamide (B)
Melting point: 262.degree.-263.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.12 (12H,d,J=6.8
Hz), 2.87 (2H, m), 3.80 (2H,s), 6.45 (1H,s), 7.10-7.70 (10H,m), 8.11
(1H,d,J=9.0 Hz), 9.05 (1H,s)
Elemental analysis (for C.sub.29 H.sub.29 N.sub.2 OCl): Calculated (%): C,
76.22; H, 6.40; N, 6.13 Found (%): C, 75.93; H, 6.65; N, 6.44
EXAMPLE 58
3,4-cis-N-(2,4-Difiuorophenyl)-3,4-dihydro-6-methyl-2-oxo-4-phenyl-2H-1-ben
zopyran-3-acetamide (A)
Melting point: 194.degree.-196.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 59
3,4-cis-6-Chloro-N-(2,4-difiuorophenyl)-3,4-dihydro-2-oxo-4-phenyl-2H-1-ben
zopyran-3-acetamide (A)
Melting point: 182.degree.-184.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 60
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1,6-dimethyl-
2-oxo-4-phenyl-3-quinolineacetamide (A)
Melting point: 251.degree.-252.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.90-1.30, 1.17
(total 12H,m,d,J=7.0 Hz), 2.17, 2.21 (total 3H, each s), 2.61 (1H,dd,J=15,
6.2 Hz), 2.71 (1H, dd, J=15, 5.4 Hz), 3.06 (2H,m), 3.30-3.50 (1H,m), 3.35,
3.43 (total 3H, each s), 4.27, 4.38 (total 1H, each d,J=10Hz, J=11 Hz),
6.46, 6.59 (total 1H, each s), 6.80-7.40 (11H,m)
EXAMPLE 61
3,4-trans-N-›2,6-Bis(1-methylethyl)phenyl!-3-(6-chloro-1,2,3,4-tetrahydro-1
-methyl-2-oxo-4-phenylcluinolin-3-yl)propionamide (A)
Melting point: 178.degree.-180.5.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.13 (6H,d,J=4.0 Hz), 1.16
(6H,d,J=3.2 Hz), 1.70-2.30 (2H,m), 2.45-2.58 (2H,m), 2.92-3.20 (3H,m),
3.41 (3H,s), 4.01 (1H,d,J=4.8 Hz), 6.90-7.40 (11H,m), 7.54 (1H,bs)
EXAMPLE 62
3,4-trans-3-(6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylquinolin-3-
yl)-N-(2,4,6-trimethoxyphenyl)propionamide (A) A white foam NMR (200 MHz,
CDCl.sub.3) ppm: 1.67-2.20 (2H,m), 2.36-2.70 (2H,m), 3.20-3.50 (1H, m),
3.39 (3H,s), 3.66 (6H,s), 3.79 (3H,s), 3.98 (1H,bd), 6.11 (2H,s),
6.90-7.40 (9H,m)
EXAMPLE 63
N-(2,4-Difiuorophenyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-3-qui
noxalineacetamide (A)
Melting point: 94.5.degree.-95.0.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.26 (3H,s), 2.60
(1H,dd,J=15, 8.5 Hz), 2.77 (1H,dd,J=15, 5.5 Hz), 3.43 (3H,s), 5.01
(1H,dd,J=8.5, 5.5 Hz), 6.76-7.32 (10H,m), 7.87 (1H,bs), 8.25 (1H,m)
EXAMPLE 64
N-›2,6-Bis(1-methylethyl)phenyl!-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-4-ph
enyl-3-quinoxalineacetamide (A)
Melting point: 186.5.degree.-187.5.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3)ppm: 1.08 (6H,d,J=6.6 Hz), 1.15
(6H,d,J=7.0 Hz), 2.28 (3H,s), 2.59 (1H,dd,J=15, 9.4 Hz), 2.81 (1H,dd,J=15,
4.6 Hz), 3.06 (2H,m), 3.42 (3H,s), 5.16 (1H,dd,J=9.4, 4.6 Hz), 6.90-7.30
(12H,m)
EXAMPLE 65
1,2,3,4-Tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-3
-quinoxalineacetamide (A)
Melting point: 237.degree.-238.degree. C. (recrystallized from
THF-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.26 (3H,s), 2.49
(1H,dd,J=14, 10 Hz), 2.71 (1H,dd,J=14, 3.6 Hz), 3.41 (3H,s), 3.63 (6H,s),
3.79 (3H,s), 5.11 (1H,dd, J=10, 3.6 Hz), 6.11 (2H,s), 6.68 (1H,bs),
6.87-7.28 (8H,m)
EXAMPLE 66
N-(2,6-Dimethoxyphenyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-3-qu
inoxalineacetamide (A)
Melting point: 139.5.degree.-140.5.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.26 (3H,s),
2.40-2.80 (2H,m), 3.41 (3H,s), 3.67 (6H,s), 5.10 (1H,bdd), 6.54
(2H,d,J=8.4 Hz), 6.80-7.30 (10 H,m)
EXAMPLE 67
6-Chloro-N-(2,6-dimethoxyphenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl
-3-quinoxalineacetamide (A)
Melting point: 212.5.degree.-213.2.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.35-2.90 (2H,m),
3.41 (3H,s), 3.69 (6H,s), 5.08 (1H,m), 6.53 (2H,d,J=8.0 Hz), 6.72 (1H,bs),
6.95-7.30 (9H,m)
EXAMPLE 68
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quin
olineacetamide (A)
Melting point: 333.degree.-337.degree. C. (recrystallized from
methanol-chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3
-DMSO-d.sub.6) ppm: 1.11 (12H,d,J=7.0 Hz), 3.54 (2H,s), 7.0-7.6 (11H,m),
8.84 (1H,b), 12.2 (1H,b)
EXAMPLE 69
1,2-Dihydro-1,6-dimethyl-2-oxo-4-phenyl-N-(2,4,6-trimethoxyphenyl)-3-quinol
ineacetamide (A)
Melting point: 275.5.degree.-277.0.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.28 (3H,s), 3.54
(2H,s), 3.73 (3H,s), 3.77 (6H,s), 3.86 (3H,s), 6.10 (2H,s), 6.96 (1H,bs),
7.25-7.55 (8H,m)
EXAMPLE 70
N-(2,6-Dimethoxyphenyl)-1,2-dihydro-1,6-dimethyl-2-oxo-4-phenyl-3-quinoline
acetamide (A)
Melting point: 212.0.degree.-213.5.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.28 (3H,s), 3.54
(2H,s), 3.76 (6H,s), 3.86 (3H,s), 6.53 (2H,d,J=8.4 Hz), 6.96 (1H,bs), 7.10
(1H,t,J=8.4 Hz), 7.30-7.60 (8H,m)
EXAMPLE 71
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-2-methoxy-4-phenyl-3-quinolineace
tnmide (A)
Melting point: 256.degree.-259.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.14 (12H,d,J=7.0 Hz), 3.69
(2H,s), 4.19 (3H,s), 7.1-7.2 (2H,m), 7.2-7.4 (5H,m), 7.5-7.6 (3H,m), 7.84
(1H,m)
EXAMPLE 72
6-Chloro-N-(2,6-dimethoxyphenyl)-2-methoxy-4-phenyl-3-quinolineacetamide
(A)
Melting point: 220.degree.-222.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 3.63 (2H, b), 3.79 (6H, s),
4.18 (3H, s), 6.55 (2H, d, J=8.6 Hz), 7.15 (1H, m), 7.28 (1H, m), 7.3-7.5
(2H, m), 7.5-7.6 (4H, m), 7.83 (1H, d, J=9.0 Hz)
EXAMPLE 73
N-(2,4-Difluorophenyl)-4-(2-methoxyphenyl)-1-oxo-1H-2-benzopyran-3-acetamid
e (A)
Melting point: 214.degree.-216.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.51 (2H, s), 3.70
(3H, s), 6.8-6.9 (2H, m), 6.96 (1H, d, J=10.4 Hz), 7.0-7.2 (2H, m), 7.26.
(1H, m), 7.4-7.7 (3H, m), 7.75 (1H, b), 8.15 (1H, m), 8.36 (1H, dd, J=7.6
Hz, 1.2 Hz)
EXAMPLE 74
N-(2,6-Dimethoxyphenyl)-4-(2-methoxyphenyl)-1-oxo-1H-2-benzopyran-3-acetami
de (A)
Melting point: 210.degree.-213.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.46 (2H, m), 3.68
(3H, s), 3.77 (6H, s), 6.54 (2H, d, J=8.4 Hz), 6.93 (1H, d, J=8.2 Hz),
7.0-7.2 (3H, m), 7.35 (1H, dd, J=7.4 Hz, 1.6 Hz), 7.4-7.6 (3H, m), 8.35
(1H, m)
EXAMPLE 75
4-(2-Methoxyphenyl)-1-oxo-N-(2,4,6-trimethoxyphenyl)-1H-2-benzopyran-3-acet
amide (A)
Melting point: 229.degree.-231.degree. C. (recrystallized from ethyl
acetate-chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.47
(2H, m), 3.67 (3H, s), 3.76 (3H, s), 3.78 (6H, s), 6.11 (2H, s), 6.9-7.2
(3H, m), 7.35 (1H, d, J=6.8 Hz), 7.4-7.6 (3H, m), 8.36 (1H, m)
EXAMPLE 76
6-Chloro-N-(2,6-dimethoxyphenyl)-1-oxo-4-phenyl-1H-2-benzopyrau-3-acetamide
(A)
Melting point: 245.degree.-247.degree. C. (recrystallized from
chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.45 (2H, m),
3.78 (6H, s), 6.54 (2H, d, J=8.4 Hz), 7.01 (1H, d, J=1.4 Hz), 7.18 (1H, t,
J=8.6 Hz), 7.4-7.6 (6H, m), 8.27 (1H, d, J=8.4 Hz)
EXAMPLE 77
6-Chloro-N-(2,6-ethoxyphenyl)-1-oxo-4-phenyl-1H-2-benzopyran-3-acetamide
(B)
Melting point: 209.degree.-210.degree. C. (recrystallized from ethanol) NMR
(200 MHz, CDCl.sub.3) ppm: 1.31 (6H, t, J=7 Hz), 3.44 (2H, b), 4.01 (4H,
q, J=7Hz), 6.52 (2H, d, J=8.4 Hz), 7.02-7.52 (9H, m), 8.27 (1H, d, J=8.4
Hz)
EXAMPLE 78
6-Chloro-N-›4-(N,N-dimethylamino)phenyl!-2-oxo-4-phenyl-2H-1-benzopyran-3-a
cetamide (A)
Melting point: 220.degree.-222.degree. C. (recrystallized from ethyl
acetate-chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.90
(6H, s), 3.42 (2H, s), 6.68 (2H, d, J=9.0 Hz), 7.04 (1H, d, J=2.0 Hz),
7.3-7.6 (9H, m), 7.95 (1H, b)
EXAMPLE 79
6-Chloro-N-(2,6-dimethoxyphenyl)-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamide
(A)
Melting point: 245.degree.-247.degree. C. (recrystallized from
chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.47 (2H, b),
3.78 (6H, s), 6.55 (2H, d, J=8.4 Hz), 7.03 (1H, d, J=1.8 Hz), 7.16 (1H, t,
J=8.4 Hz), 7.3-7.5 (4H, m), 7.5-7.6 (3H, m)
EXAMPLE 80
N-›4-(N,N-Dimethylamino)phenyl!-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-a
cetamide (A)
Melting point: 227.degree.-228.degree. C. (recrystallized from ethyl
acetate-chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.27
(3H, s), 2.89 (6H, s), 3.41 (2H, s), 6.68 (2H, d, J=8.8 Hz), 6.84 (1H, s),
7.3-7.4 (6H, m), 7.5-7.6 (3H, m), 8.18 (1H, b)
EXAMPLE 81
N-(2,6-Dimethoxyphenyl)-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetamid
(A)
Melting point: 257.degree.-258.degree. C. (recrystallized from
chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.27 (3H, s),
3.46 (2H, b), 3.77 (6H, s), 6.54 (2H, cl, J=8.4 Hz), 6.83 (1H, s), 7.14
(1H, t, J=8.4 Hz), 7.2-7.3 (2H, m), 7.4-7.6 (5H, m)
EXAMPLE 82
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-ben
zopyran-3-acetamide (A)
Melting point: 241.degree.-243.degree. C. (recrystallized from
acetone-methanol) NMR (200 MHz, CDCl.sub.3) ppm: 1.13 (total 12H, d, J=6.8
Hz, 1.0-1.1, m), 2.03, 2.09 (total 3H, each s), 3.00 (2H, m), 3.38 (1H, d,
J=13.8 Hz), 3.58 (1H, d, J=13.8 Hz), 6.85 (1H, d, J=2.4 Hz), 7.1-7.2 (3H,
m), 7.3-7.5 (6H, m)
EXAMPLE 83
6-Chloro-N-(2,4-difluorophenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-
acetamide (A)
Melting point: 186.degree.-188.degree. C. (recrystallized from
chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.09 (3H, s),
3.35 (1H, d, J=14.1 Hz), 3.50 (1H, d, J=13.9 Hz), 6.7-6.9 (3H, m), 7.17
(1H, m), 7.3-7.5 (5H, m), 8.0-8.2 (2H, m)
EXAMPLE 84
6-Chloro-N-(2,6-dimethoxyphenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3
-acetamide (A)
Melting point: 196.degree.-198.degree. C. (recrystallized From ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.09 (3H, s), 3.4
(2H, m), 3.75 (6H, s), 6.53 (2H, d, J=8.4 Hz), 6.82 (1H, d, J=2.2 Hz),
7.14 (1H, t, J=8.4 Hz), 7.2 (1H, m), 7.3-7.5 (5H, m)
EXAMPLE 85
6-Chloro-4-(2-methylphenyl)-2-oxo-N-(2,4,6-trimethoxyphenyl)-2H-1-benzopyra
n-3-acetamide (A)
Melting point: 183.degree.-185.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.08 (3H, s), 3.4
(2H, m), 3.74 (3H, s), 3.78 (6H, s), 6.09 (2H, s), 6.81 (1H, m), 7.2-7.5
(6H, m)
EXAMPLE 86
6-Chloro-N-(2,6-dimethylphenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-
acetamide (A)
Melting point: 235.degree.-238.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.10 (3H, s), 2.17
(6H, s), 3.36 (1H, d, J=13.8 Hz), 3.54 (1H, d, J=14.0 Hz), 6.86 (1H, d,
J=2.4Hz), 7.04 (31H, m), 7.2-7.3 (1H, m), 7.3-7.5 (5H, m)
EXAMPLE 87
6-C
hloro-4-(2-methylphenyl)-2-oxo-N-(2,4,6-trimethylphenyl)-2H-1-benzopyran-3
-acetamide (A)
Melting point: 238.degree.-241.degree. C. (recrystallized from ethyl
acetate-acetone-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.10 (3H,
s), 2.12 (6H, s), 2.23 (3H, s), 3.34 (1H, d, J=14.0 Hz), 3.52 (1H, d,
J=13.8 Hz), 6.85 (3H, m), 7.2-7.3 (1H, m), 7.3-7.5 (5H, m)
EXAMPLE 88
6-Chloro-N-(2,6-diethoxyphenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-
acetamide (A)
Melting point: 200.degree.-202.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.29 (6H, t, J=7.0
Hz), 2.08 (3H, s), 3.44 (2H, b), 8.98 (4H, q, J=7.0 Hz), 6.50 (2H, d,
J=8.4 Hz), 6.82 (1H, m), 7.09 (1H, t, J=8.6 Hz), 7.2-7.5 (6H, m)
EXAMPLE 89
6-Chloro-N-(2,6-diethoxy-4-fluorophenyl)-4-(2-methylphenyl)-2-oxo-2H-1-benz
opyran-3-acetamide (A)
Melting point: 208.degree.-209.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.29 (6H, t, J=7.0
Hz), 2.08 (3H, s), 3.32 (1H, bd), 3.53 (1H, bd), 3.93 (4H, q, J=7.0 Hz),
6.23 (2H, d, J=11 Hz), 6.83 (2H, bs), 7.19-7.50 (7H, m)
EXAMPLE 90
N-›3,5-Bis(trifluoromethyl)phenyl!-6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-b
enzopyran-3-acetamide (A)
Melting point: 205.degree.-206.degree. C. (recrystalized from ethyl
acetate-isopropyl ether)
EXAMPLE 91
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methylphenyl)-1-quinolineace
tamide (B)
Melting point: 208.degree.-210.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.11 (6H, d, J=7.0
Hz), 1.13 (6H, d, J=7.0 Hz), 1.97 (3H, s), 2.85 (2H, m), 3.60 (1H, d,
J=16Hz), 3.79 (1H, d, J=16 Hz), 6.43 (1H, bs), 7.00-7.70 (5H, m), 8.12
(1H, d, J=8.8 Hz), 9.08 (1H, s)
EXAMPLE 92
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-be
nzopyran-3-acetamide (A)
Melting point: 303.degree.-305.degree. C. (recrystallized from chloroform)
NMR (200 MHz, CDCl.sub.3) ppm: 1.13 (dd, 12H, J=2.4, 6.8 Hz), 2.90-3.05
(m, 2H), 3.38 (d, 1H, J=13.8 Hz), 3.65 (d, 1H, J=14.0 Hz), 3.71 (s, 3H),
6.95 (d, 1H, J=2.4 Hz), 7.06-7.18 (m, 4H), 7.22-7.30 (m, 2H), 7.37 (d, 1H,
J=8.8 Hz), 7.44-7.58 (m, 2H)
EXAMPLE 93
6-Chloro-N-(2,6-diethoxyphenyl)-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3
-acetamide (A)
Melting point: 226.degree.-227.degree. C. (recrystallized from ethyl
acetate-methanol) NMR (200 MHz, CDCl.sub.3) ppm: 1.29 (6H, t, J=7.0 Hz),
3.20-3.38 (1H, m), 3.56-3.70 (1H, m), 3.69 (3H, s), 3.98 (4H, q, J=7.0
Hz), 6.51 (2H, d, J=8.4 Hz), 6.92 (1H, d, J=2.2 Hz), 7.00-7.18 (3H, m),
7.28-7.56 (4H, m)
EXAMPLE 94
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-2-oxo-4-(2-trifluoromethylphenyl)
-2H-1-benzopyran-3-acetamide (A)
Melting point:246.degree.-247.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 1.12 (12H, t, J=6.4 Hz), 2.88-3.06
(2H, m), 3.07 (1H, d, J=14.0 Hz), 3.79 (1H, d, J=13.8 Hz), 6.72 (1H, d,
J=2.4 Hz), 7.13 (1H, d, J=7.0 Hz), 7.20-7.30 (1H, m), 7.32-7.50 (4H, m),
7.64-7.74 (2H, m), 7.84-7.92 (1H, m)
EXAMPLE 95
6-Chloro-N-(2,6-diethoxyphenyl)-2-oxo-4-(2-trifluoromethylphenyl)-2H-1-benz
opyran-3-acetamide (A)
Melting point: 197.degree.-199.degree. C. (recrystallized from ethyl
ether--ethyl acetate) NMR (200 MHz, CDCl.sub.3) ppm: 1.27 (6H, t, J=7.0
Hz), 2.94-3.08 (1H, m), 3.70-3.88 (1H, m), 3.97 (4H, q, J=7.0 Hz), 6.50
(2H, d, j=8.4Hz), J=8.4 Hz), 6.68 (1H, s), 7.09 (1H, t, J=8.0 Hz), 7.32
(2H, d, J=8.6 Hz), 7.44 (1H, dd, J=2.2, 8.6 Hz), 7.46-7.58 (1H, m),
7.58-7.76 (2H, m), 7.86 (1H, d, J=7.6 Hz)
EXAMPLE 96
6-Chloro-N-(2,6-diethoxy-4-fluorophenyl)-2-oxo-4-(2-trifluoromethylphenyl)-
2H-1-benzopyran-3-acetamide (A)
Melting point: 199.degree.-200.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.28 (6H, t, J=7.0 Hz), 3.01
(1H, bd), 3.75 (1H, bd), 3.93 (4H, q, J=7.0 Hz), 6.23 (2H, d, J=11 Hz),
6.69 (1H, bs), 7.18-7.90 (7H, m)
EXAMPLE 97
6-Chloro-4-(2-methoxyphenyl)-2-oxo-N-(2,4,6-trifluolophenyl)-2H-1-benzopyra
n-3-acetamide (A)
Melting point: 243.degree.-245.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 3.41 (1H, d, J=14.2 Hz), 3.55 (1H,
d, J=14.0 35 Hz), 3.73 (3H, s), 6.70 (2H, ddd, J=2.0, 7.6, 8.8 Hz), 6.97
(1H, d, J=2.4 Hz), 7.09 (1H, d, J=8.6 Hz), 7.17 (1H, d, J=7.0 Hz), 7.21
(1H, dd, J=2.0, 4.2 Hz), 7.36 (1H, d, J=8.8 Hz), 7.48 (1H, dd, J=2.4 Hz),
7.54 (1H, ddd, J=2.2, 7.0, 8.4 Hz), 7.75 (1H, bs)
EXAMPLE 98
6-Chloro-N-(2,6-dimethoxybenzyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3
-acetamide
6-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid was reacted
with 2,6-dimethoxybenzylamine by a method similar to Example 1(A) to yield
the title compound.
Melting point: 194.degree.-196.degree. C. (recrystallized from ethyl
acetate-methanol-isopropyl ether) NMR (200 MHz, CDCl3) ppm: 2.05 (3H, s),
3.11 (1H, d, J=14.0 Hz), 3.27 (1H, d, J=14.0 Hz), 3.81 (6H, s), 4.49 (2H,
d, J=5.4 Hz), 6.35 (1H, b), 6.54 (2H, d, J=8.4 Hz), 6.81 (1H, d, J=2.2
Hz), 7.2-7.5 (7H, m)
EXAMPLE 99
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-1-methyl-4-phenyl-3-q
uinolineacetamide
A mixture of the compound obtained in Example 57 (150 mg), dioxane (5 ml)
and methyl iodide (1.5 ml) was refiuxed for 2 hours while heating. Upon
solvent removal by distillation, a quaternary salt (iodide), resulting
from 1-methylation of the compound of Example 57, was obtained as yellow
crystals. To a solution of this quaternary salt in methanol (5 ml) was
added sodium borohydride (30 mg) at 0.degree. C., followed by stirring for
20 minutes. The reaction mixture was acidified with dilute hydrochloric
acid and then alkalinized with aqueous potassium carbonate, followed by
extraction with ethyl acetate. The extract was washed with water and
dried, after which the solvent was distilled off, to yield the title
compound as colorless crystals (90 mg).
Melting point: 192.degree.-194.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.15 (12H, d,
J=6.6 Hz), 2.86 (3H, s), 2.95 (2H, m), 3.17 (2H, s), 4.08 (2H, s),
6.45-6.58 (2H, m), 7.00-7.50 (10H, m)
Elemental analysis (for C.sub.30 H.sub.33 N.sub.2
OCl.multidot.0.2i-Pr.sub.2 O):
Calculated (%): C, 75.94; H, 7.31; N, 5.68
Found (%): C, 75.71; H, 7.13; N, 6.02
EXAMPLE 100
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-1,2-dihydro-1-methyl-4-(2-methylp
henyl)-3-quinolineacetamide
N-›2,6-Bis(1-methylethyl)phenyl!-6-chloro-4-(2-methylphenyl)-3-quinolineace
tamide (Example 91) was reacted by a method similar to Example 99 to yield
the title compound.
Melting point: 159.5.degree.-160.5.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.14 (6H, d, J=3.6
Hz), 1.17 (6H, d, J=3.6 Hz), 2.15 (3H, s), 2.87 (3H, s), 2.95 (2H, m),
3.05 (2H, m), 4.11 (2H, s), 6.36(1H, d, J=2.2 Hz), 6.53 (1H, d, J=8.8 Hz),
6.97 (1H, bs), 7.00-7.40 (8H, m)
EXAMPLE 101
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2-methylphenyl)-
1-oxo-3-isoquinolinecarboxamide
To a solution of
2-methyl-4-(2-methylphenyl)-l(2H)-isoquinolinone-3-carboxylic acid (293
mg) fn THF (10 ml) were added oxalyl chloride (0.104 ml) and DMF (one
drop) at room temperature, followed by stirring for 1 hour. After the
solvent was distilled off, the residue was dissolved in dichloromethane
(10 ml). To this solution was added a solution of
3,5-bis(trifluoromethyl)benzylamine (340 mg) and triethylamine (0.154 ml)
in dichloromethane (5 ml), followed by stirring at room temperature for 5
hours. After the solvent was distilled off, ethyl acetate was added to the
residue. This mixture was washed successively with water, dilute
hydrochloric acid, water, aqueous sodium hydrogen carbonate and water and
then dried, after which the solvent was distilled off, to yield fie title
compound as colorless crystals (250 mg).
Melting point: 168.5.degree.-170.0.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.02 (3H, s), 3.59 (3H, s),
4.24 (1H, dd, J: 14.6, 5.6 Hz), 4.42 (1H, dd, J=14.6, 5.6 Hz), 6.15 (1H,
b, NH), 6.89 (1H, m), 7.09 (4H, m), 7.50 (4H, m), 7.79 (1H, s), 8.44 (1H,
m)
Elemental analysis (for C.sub.27 H.sub.20 N.sub.2 O.sub.2 F.sub.6):
Calculated: C, 62.55; H, 3.89; N, 5.40
Found: C, 62.29; H, 4.12; N, 5.68
EXAMPLE 102
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-4-(2-methylphen
yl)-1-oxo-3-isoquinolinecarboxamide
Method C
A mixture of the compound (156 mg) obtained in Example 101, sodium hydride
(60% in oil) (12 mg) and DMF (5 ml) was stirred at room temperature for 30
minutes, and methyl iodide (0.5 ml) was added, followed by stirring at
room temperature for 1 hour. The reaction mixture was poured into water
and extracted with ethyl acetate, and the extract was washed with water
and then dried, followed by solvent removal by distillation, to yield the
title compound as colorless crystals (156 mg).
Method D
Using N-›3,5-bis(trifluoromethyl)benzyl!methylamine in place of
3,5-bis(trifluoromethyl)benzylamine,
2-methyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylic acid was
amidated in substantially the same manner as in Example 101 to yield the
title compound as colorless crystals.
Melting point: 76.degree.-78.degree. C. (recrystallized from hexane) NMR
(200 MHz, CDCl.sub.3) ppm: 2.01 (1.5H, s), 2.12 (1.5H, s), 2.77 (1.5H, s),
2.97 (1.5H, s), 3.58 (1.5H, s), 3.60 (1.5H, s), 4.10 (0.5H, d, J=14.4 Hz),
4.26 (0.5H, d, J=14.4 Hz), 4.78 (0.5H, d, J=14.4 Hz), 4.96 (0.5H, d,
J=14.4 Hz), 6.86-7.02 (2H, m), 7.12-7.32 (3H, m), 7.48-7.57 (4H, m), 7.79
(1H, s), 8.51 (1H, m)
Elemental analysis (for C.sub.28 H.sub.22 N.sub.2 O.sub.2 F.sub.6):
Calculated: C, 63.16; H, 4.16; N, 5.26
Found: C, 63.40; H, 4.37; N, 5.02
The compounds of Examples 103 to 188 were obtained by reacting
1(2H)-isoquinoline-3-carboxylic acids having respective corresponding
substituents with amines in the same manner (amidation) as in Example 101
or method D of Example 102, or by reacting amide compounds having
respective corresponding substituents with alkylating agents in the same
manner (alkylation) as method C of Example 102. With respect to Examples
103 to 188, the name of the compound is followed by the symbol ›C! when
the compound was produced by alkylation, other production examples being
based on amidation.
EXAMPLE 103
N-Benzyl-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoquinolineca
rboxamide
Melting point: 172.degree.-173.5.degree. C. (recrystallized from ethyl
acetate) NMR (200 MMz, CDCl.sub.3) ppm: 2.22 (3H, s), 2.86 (3H, s), 3.60
(3H, s), 3.96 (1H, d, J=14.6 Hz), 5.05 (1H, d, J=14.6 Hz), 6.66 (1H, dd,
J=8.0, 2.0 Hz), 6.92-7.56 (11H, m), 8.53 (1H, m)
Elemental analysis (for C.sub.26 H.sub.24 N.sub.2 O.sub.2
.multidot.0.2H.sub.2 O):
Calculated: C, 78.05; H, 6.15; N, 7.00
Found: C, 78.25; H, 6.11; N, 7.00
EXAMPLE 104
1,2-Dihydro-N-(2-methoxybenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-iso
quinolinecarboxamide ›C!
Melting point: 153.degree.-154.5.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.04 (1.5H, s), 2.19 (1.5H, s),
2.74 (1.5H, s), 2.89 (1.5H, s), 3.59 (1.5H, s), 3.62 (1.5H, s), 3.77
(1.5H, s), 3.78 (1.5H, s), 4.35 (1H, dd, J=15.2, 7.6 Hz), 4.73 (1H, dd,
J=15.0, 5.8 Hz), 6.08 (0.5H, d, J=7.2 Hz), 6.24 (0.5H, d, J=7.6 Hz),
6.56-7.56 (10H, m), 8.51 (1H, m)
Elemental analysis (for C.sub.27 H.sub.26 N.sub.2 O.sub.3):
Calculated: C, 76.03; H, 6.14; N, 6.57
Found: C, 75.66; H, 6.20; N, 6.56
EXAMPLE 105
N-(2-Chlorobenzyl)-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoq
uinolinecarboxamide ›C!
Melting point: 143.degree.-144.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.05 (1.5H, s), 2.20 (1.5H, s),
2.79 (1.5H, s), 2.94 (1.5H, s), 3.63 (1.5H, s), 3.65 (1.5H, s), 4.26 (1H,
d, J=15.4 Hz), 5.08 (1H, d, J=16.2 Hz), 5.92 (0.5H, d, J=8.0.Hz), 6.07
(0.5H, d, J=8.0 Hz), 6.89-7.59 (10H, m), 8.53 (1H, m)
Elemental analysis (for C.sub.26 H.sub.23 N.sub.2 O.sub.2 Cl):
Calculated: C, 72.47; H, 5.38; N, 6.50
Found: C, 72.46; H, 5.37; N, 6.73
EXAMPLE 106
1,2-Dihydro-N-(3,5-dimethylbenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-
isoquinolinecarboxamide ›C!
Melting point: 135.degree.-136.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.01 (1.5H, s), 2.20 (1.5H,
s), 2.25 (6H, s), 2.66 (1.5H, s), 2.84 (1.5H, s), 3.58 (1.5H, s), 3.61
(1H, s), 4.08 (1H, dd, J=14.0, 8.8 Hz), 4.71 (1H, t, J=12.8 Hz), 6.45 (1H,
s), 6.52 (1H, s), 6.87-7.55 (8H, m), 8.52 (1H, m)
Elemental analysis (for C.sub.28 H.sub.28 N.sub.2 O.sub.2):
Calculated: C, 79.22; H, 6.65; N, 6.60
Found: C, 78.85; H, 6.68; N, 6.64
EXAMPLE 107
N-Ethyl-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3
-isoquinolinecarboxamide ›C!
Melting point: 119.degree.-120.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 0.97 (0.9H, t, J=7.2 Hz),
1.12 (2.1H, t, J=7.2 Hz), 2.01 (0.9H, s), 2.19 (2.1H, s), 2.85-3.20 (2H,
m), 3.62 (2.1H, s), 3.63 (0.9H, s), 3.79 (3H, s), 4.30 (0.7H, d, J=15.8
Hz), 4.35 (0.3H, d, J=15.8 Hz), 4.87 (0.3H, d, J=15.8 Hz), 4.93 (0.7H, d,
J=15.8 Hz), 5.88 (1H, m), 6.56-7.58 (10H, m), 8.53 (1H, m)
Elemental analysis (for C.sub.28 H.sub.28 N.sub.2 O.sub.3):
Calculated: C, 76.34; H, 6.41; N, 6.36
Found: C, 76.57; H, 6.48; N, 6.51
EXAMPLE 108
1,2-Dihydro-N-(2-methoxybenzyl)-N,2-dimethyl-1-oxo-4-phenyl-3-isoquinolinec
arboxamide ›C!
Melting point: 146.5.degree.-147.5.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.72 (3H, s), 3.62 (3H, s), 3.77
(3H, s), 4.40 (1H, d, J=15.2 Hz), 4.64 (1H, d, J=15.2 Hz); 6.23 (1H, d,
J=6.2 Hz), 6.69 (1H, t, J=7.4 Hz), 6.78 (1H, d, J=8.4 Hz), 7.15-7.31 (3H,
m), 7.41-7.60 (6H, m), 8.52 (1H, m)
Elemental analysis (for C.sub.26 H.sub.24 N.sub.2 O.sub.3):
Calculated: C, 75.71; H, 5.86; N, 6.79
Found: C, 75.43; H, 5.83; N, 6.90
EXAMPLE 109
1,2-Dihydro-N-(4-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoli
necarboxamide
Melting point: 240.degree.-242.5.degree. C. (recrystallized from
THF-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.22 (3H, s), 2.34
(3H, s), 3.53 (3H, s), 3.79 (3H, s), 4.17 (2H, d, J=5.4 Hz), 6.15 (1H, bt,
J=5.4 Hz), 6.72 (4H, s), 6.89 (1H, s), 7.30-7.50 (5H, m), 8.14 (1H, s)
Elemental analysis (for C.sub.27 H.sub.26 N.sub.2 O.sub.3):
Calculated: C, 76.03; H, 6.14; N, 6.57
Found: C, 75.70; H, 6.32; N, 6.47
EXAMPLE 110
1,2-Dihydro-N-(2-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoli
necarboxamide
Melting point: 229.degree.-231.5.degree. C. (recrystallized from THF-ethyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.23 (3H, s), 2.36 (3H, s), 3.57
(3H, s), 3.75 (3H, s), 4.24 (2H, d, J=6.4 Hz), 6.21 (1H, bt), 6.70-6.90
(3H, m), 6.93 (1H, s), 7.15-7.30 (6H, m), 8.21 (1H, s)
Elemental analysis (for C.sub.27 H.sub.26 N.sub.2 O.sub.3):
Calculated: C, 76.03; H, 6.14; N, 6.57
Found: C, 75.95; H, 6.18; N, 6.53
EXAMPLE 111
1,2-Dihydro-N-(2-methoxybenzyl)-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoqui
nolinecarboxamide ›C!
Melting point: 123.degree.-124.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.26 (3H, s), 2.40
(3H, s), 2.70 (3H, s), 3.60 (3H, s), 3.77 (3H, s), 4.38 (1H, d, J=15 Hz),
4.64 (1H, d, J=15 Hz), 6.20 (1H, dd, J=7.2, 1.4 Hz), 6.69 (1H, dt, J=1.0,
7.6 Hz), 6.79 (1H, d, J=7.4 Hz), 6.97 (1H, s), 7.10-7.35 (2H, m),
7.35-7.55 (4H, m), 8.27 (1H, s)
Elemental analysis (for C.sub.28 H.sub.28 N.sub.2 O.sub.3):
Calculated: C, 76.34; H, 6.41; N, 6.36
Found: C, 76.00; H, 6.70; N, 6.06
EXAMPLE 112
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2,6,7-
tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide ›C!
Melting point: 148.degree.-149.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.26 (3H, s), 2.40 (3H, s),
2.76 (3H, s), 3.58 (3H, s), 4.26 (1H, d, J=15 Hz), 4.74 (1H, d, J=15 Hz),
6.94 (1H, s), 7.15-7.45 (5H, m), 7.50 (2H, s), 7.80 (1H, s), 8.27 (1H, s)
Elemental analysis (for C.sub.29 H.sub.24 N.sub.2 O.sub.2 F.sub.6):
Calculated: C, 63.73; It, 4.43; N, 5.13
Found: C, 63.98; H, 4.59; N, 5.13
EXAMPLE 113
1,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarbo
xamide
Melting point: 220-221.degree. C. (recrystallized from ethyl acetate)
EXAMPLE 114
1,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquin
olinecarboxamide
Melting point: 237.degree.-239.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 115
N-(2-Chlorobenzyl)-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquino
linecarboxamide
Melting point: 230.degree.-231.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 116
1,2-Dihydro-N-(3,5-dimethylbenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoq
uinolinecarboxamide
Melting point: 176.5.degree.-177.5.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 117
N-Benzyl-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-
3-isoquinolinecarboxamide ›A!
Melting point: 118.degree.-120.degree. C. (recrystallized from ethyl
ether-hexane)
EXAMPLE 118
1,2-Dihydro-N-(4-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquin
olinecarboxamide
Melting point: 178.degree.-179.5.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 119
N-Benzyl-1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinecarbox
amide
Melting point: 170.degree.-172.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 120
N-Benzyl-4-(2-ethylphenyl)-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinecarboxa
mide
Melting point: 177.degree.-179.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 121
4-(2-Ethylphenyl)-1,2-dihydro-N-(4-methoxybenzyl)-2-methyl-1-oxo-3-isoquino
linecarboxamide
Melting point: 195.degree.-196.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 122
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2,6-dimethylphen
yl)-1-oxo-3-isoquinolinecarboxamide
Melting point: 225.5.degree.-226.5.degree. C. (recrystallized from ethyl
acetate)
Elemental analysis (for C.sub.28 H.sub.22 N.sub.2 O.sub.2 F.sub.6):
Calculated: C, 63.16; H, 4.16; N, 5.26
Found: C, 62.94; H, 4.18; N, 5.15
EXAMPLE 123
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-4-(2,6-dimethylphenyl)-N,2-d
imethyl-1-oxo-3-isoquinolinecarboxamide ›C!
Melting point: 121.degree.-124.degree. C. (recrystallized from ethyl ether)
EXAMPLE 124
1,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2,6-dimethylphenyl)-1-oxo-3-iso
quinolinecarboxamide
Melting point: 175.degree.-177.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 125
1,2-Dihydro-4-(2,6-dimethylphenyl)-N-(2-methoxybenzyl)-N,2-dimethyl-1-oxo-3
-isoquinolinecarboxamide ›C!
Melting point: 192.degree.-194.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
EXAMPLE 126
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-N-(2-phenylethyl)-3-isoquinoline
carboxamide
Melting point: 225.degree.-226.5.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 127
1,2-Dihydro-2,6,7-trimethyl-N-(4-methylbenzyl)-1-oxo-4-phenyl-3-isoquinolin
ecarboxamide
Melting point: 240.degree.-242.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 128
1,2-Dihydro-N-(3-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoli
necarboxamide
Melting point: 201.degree.-203.degree. C. (recrystallized from THF-ethyl
ether)
EXAMPLE 129
N-(4-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolin
ecarboxamide
Melting point: 243.7.degree.-245.7.degree. C. (recrystallized from
THF-isopropyl ether)
EXAMPLE 130
N-(3-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolin
ecarboxamide
Melting point: 213.degree.-214.degree. C. (recrystallized from THF-ethyl
ether)
EXAMPLE 131
N-(2-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolin
ecarboxamide
Melting point: 259.5.degree.-260.5.degree. C. (recrystallized from
THF-ethyl ether)
EXAMPLE 132
1,2-Dihydro-N,2,6,7-tetramethyl-N-(4-methylbenzyl)-1-oxo-4-phenyl-3-isoquin
olinecarboxamide ›C!
Melting point: 169.8.degree.-170.8.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 133
1,2-Dihydro-N-(4-methoxybenzyl)-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoqui
nolinecarboxamide ›C!
Melting point: 201.degree.-202.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 134
N-(4-Chlorobenzyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquin
olinecarboxamide ›C!
Melting point: 175.degree.-176.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 135
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phen
yl-3-isoquinolinecarboxamide
Melting point: 92.degree.-93.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 136
1,2-Dihydro-N-›2-(2-methoxyphenyl)ethyl!-2,6,7-trimethyl-1-oxo-4-phenyl-3-i
soquinolinecarboxamide
Melting point: 214.degree.-216.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 137
1,2-Dihydro-N-›2-(2-methoxyphenyl)ethyl!-N,2,6,7-
tetramethyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide ›C!
Melting point: 110.degree.-111.degree. C. (recrystallized from ethyl
ether-hexane)
EXAMPLE 138
N-›2-(3,4-Dimethoxyphenyl)ethyl!-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinol
inecarboxamide
Melting point: 185.degree.-187.degree. C. (recrystallized from
THF-isopropyl ether)
EXAMPLE 139
6-Chloro-1,2-dihydro-N-(4-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-
3-isoquinolinecarboxamide
Melting point: 181.degree.-183.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 140
6-Chloro-1,2-dihydro-N-(4-methoxybenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-
oxo-3-isoquinolinecarboxamide ›C!
Melting point: 159.degree.-160.5.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 141
N-Benzyl-6-chloro-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoqu
inolinecarboxamide
Melting point: 151.degree.-153.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 142
7-Chloro-1,2-dihydro-N-(4-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-
3-isoquinolinecarboxamide
Melting point: 204.degree.-205.5.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 143
N-Benzyl-7-chloro-1,2-dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-isoqu
inolinecarboxamide
Melting point: 171.degree.-172.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 144
6-
Chloro-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3
-isoquinolinecarboxamide
Melting point: 200.5-202.5.degree. C. (recrystallized from ethyl acetate)
EXAMPLE 145
7-Chloro-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-
3-isoquinolinecarboxamide
Melting point: 187.degree.-188.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 146
N-Benzyl-1,2-dihydro-N,2,6,7-tetramethyl-4-(2-methylphenyl)-1-oxo-3-isoquin
olinecarboxamide
Melting point: 177.degree.-178.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 147
N-Benzyl-1,2-dihydro-4-(2,6-dimethylphenyl)-N,2,6,7-tetramethyl-1-oxo-3-iso
quinolinecarboxamide
Melting point: 186.degree.-187.5.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 148
1,2-Dihydro-N-furfuryl-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboxa
mide
Melting point: 224.degree.-225.degree. C. (recrystallized from
THF-isopropyl ether)
EXAMPLE 149
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-N-(2-pyridyl)methyl-3-isoquinoli
necarboxamide
Melting point: 218.degree.-220.degree. C. (recrystallized from THF-ethyl
ether)
EXAMPLE 150
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-N-(2-thienyl)methyl-3-isoquinoli
necarboxamide
Melting point: 256.5.degree.-258.0.degree. C. (recrystallized from
tetrahydrofuran-isopropyl ether)
EXAMPLE 151
1,2-Dihydro-N-(4-methoxybenzyl)-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-3-iso
quinolinecarboxamide ›C!
Melting point: 147.degree.-150.degree. C. (recrystallized from hexane-ethyl
acetate)
EXAMPLE 152
1,2-Dihydro-N-›2-(2-methoxyphenyl)ethyl!-2-methyl-4-(2-methylphenyl)-1-oxo-
3-isoquinolinecarboxamide
Melting point: 217.degree.-219.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 153
1,2-Dihydro-N-›2-(2-methoxyphenyl)ethyl!-N,2-dimethyl-4-(2-methylphenyl)-1-
oxo-3-isoquinolinecarboxamide ›C!
Melting point: 123.degree.-125.degree. C. (recrystallized from ethyl ether)
EXAMPLE 154
1,2-dihydro-N-(2-methoxyphenyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquin
olinecarboxamide
Melting point: 142.degree.-145.degree. C. (recrystallized from ethyl ether)
EXAMPLE 155
1,2-Dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-N-(3,4,5-trimethoxyphenyl)-3-
isoquinolinecarboxamide
Melting point: 222.5.degree.-224.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 156
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-is
oquinolinecarboxamide
Melting point: 150.degree.-152.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.55. (3H,s), 4.34
(2H, d, J=6.2 Hz), 6.68 (1H, bt), 7.12-7.50 (8H, m), 7.52 (2H, s), 7.78
(1H, s), 8.37 (1H, m)
EXAMPLE 157
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-
3-isoquinolinecarboxamide ›C!
Melting point: 144.5.degree.-146.degree. C. (recrystallized from ether) NMR
(200 MHz, CDCl.sub.3) ppm: 2.78 (3H,s), 3.61 (3H, s), 4.26 (1H, d, J=14.2
Hz), 4.75 (2H, d, J=14.2 Hz), 7.19-7.40 (6H, m), 7.51 (2H, s), 7.53-7.58
(2H, m), 7.81 (1H, s), 8.52 (1H, m)
EXAMPLE 158
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-4-(2-methoxyphenyl)-2-methyl
-1-oxo-3-isoquinolinecarboxamide
Melting point: 236.degree.-238.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 159
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-4-(2-methoxyphenyl)-N,2-dime
thyl-1-oxo-3-isoquinolinecarboxamide ›C!
Melting point: 171.degree.-173.degree. C. (recrystallized from ethyl ethyl
acetate-ether)
EXAMPLE 160
1,2-Dihydro-N-(2-methoxybenzyl)-4-(2-methoxyphenyl)-2-methyl-1-oxo-3-isoqui
nolinecarboxarnide
Melting point: 191.degree.-193.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 161
1,2-Dihydro-N-(2-methoxybenzyl)-4-(2-methoxyphenyl)-N,2-dimethyl-1-oxo-3-is
oquinolinecarboxamide ›C!
Melting point: 146.degree.-148.5.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
EXAMPLE 162
N-Benzyl-4-(2-ethylphenyl)-1,2-dihydro-N,2-dimethyl-1-oxo-3-isoquinolinecar
boxamide ›C!
A colorless oily substance
NMR (200 MHz, CDCl.sub.3) ppm: 1.04 (3H, t, J=7.6 Hz), 2.63 (2H, m), 2.83
(3H, s), 3.61 (3H, s), 3.94 (1H, d, J=14.2 Hz), 5.06 (1H, d, J=14.2 Hz),
6.60-6.65 (2H, m), 6.95-7.55 (10H, m), 8.52 (1H, m)
EXAMPLE 163
4-(2-Ethylphenyl)-1,2-dihydro-N-(4-methoxybenzyl)-N,2-dimethyl-1-oxo-3-isoq
uinolinecarboxamide ›C!
A colorless oily substance
NMR (200 MHz, CDCl.sub.3) ppm: 1.04 (3H, t, J=7.6 Hz), 2.66 (2H, m), 2.80
(3H, s), 3.59 (3H, s), 3.80 (3H, s), 3.91 (1H, d, J=14.4 Hz), 4.94 (1H, d,
J=14.4 Hz), 6.57-6.72 (4H, m), 6.94-7.19 (3H, m), 7.36-7.55 (4H, m), 8.51
(1H, m)
EXAMPLE 164
N-Benzyl-4-(2-ethylphenyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-3-isoquino
linecarboxamide
A white powder
NMR (200 MHz, CDCl.sub.3) ppm: 1.26 (3H, t, J=7.0 Hz), 2.23 (3H, s), 2.39
(3H, s), 2.65 (2H, m), 2.73 (3H, s), 3.57 (3H, s), 3.79 (1H, d, J=14.0
Hz), 4.92 (1H, d, J=14.0 Hz), 6.50-7.40 (10H, m), 8.26 (1H, s)
EXAMPLE 165
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-2-methyl-
1-oxo-3-isoquinolinecarboxamide
Melting point: 184.degree.-186.degree. C. (recrystallized from ethyl ether)
NMR (200 MHz, CDCl.sub.3) ppm: 3.59 (3H,s), 4.39 (2H, d, J=5.8 Hz), 6.32
(1H, bt, NH), 6.95 (1H, t, J=8.4 Hz), 7.10-7.37 (5H, m), 7.51 (1H, m),
7.56 (2H, s), 7.83 (1H, s), 8.45 (1H, m)
EXAMPLE 166
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N,2-dimet
hyl-1-oxo-3-isoquinolinecarboxamide (C)
Melting point: 99.degree.-101.degree. C. (recrystallized from isopropyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.83 (3H, s), 3.60 (3H, s),
4.28 (1H, d, J=14.4 Hz), 4.78 (1H, d, J=14.4 Hz), 6.93-7.02 (2H, m),
7.13-7.39 (3H, m), 7.52-7.61 (4H, m), 7.84 (1H, s), 8.52 (1H, m)
EXAMPLE 167
1,2-Dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-N-(3,4,5-trimethoxybenzyl)-3-
isoquinolinecarboxamide
Melting point: 227.degree.-228.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 168
1,2-Dihydro-N,2-dimethyl-4-(2-methylphenyl)-1-oxo-N-(3,4,5-trimethoxybenzyI
)-3-isoquinolinecarboxamide (C)
Melting point: 178.degree.-179.5.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 169
1,2-Dihydro-2-methyl-N-(4-methylbenzyl)-4-(2-methylphenyl)-1-oxo-3-isoquino
linecarboxamide
Melting point: 165.degree.-166.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
EXAMPLE 170
1,2-Dihydro-2-methyl-N-(4-methylbenzyl)-1-oxo-4-phenyl-3-isoquinolinecarbox
amide
Melting point: 216.degree.-217.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.32 (3H, s), 3.54
(3H, s), 4.19 (2H, d, J=5.4 Hz), 6.10 (1H, bt), 6.68 (2H, d, J=8.0 Hz),
7.02 (2H, d, J=8.0 Hz), 7.20 (1H, d, J=7.8 Hz), 7.31-7.56 (7H, m), 8.37
(1H, dd, J=7.2, 1.0 Hz)
EXAMPLE 171
1,2-Dihydro-2-methyl-1-oxo-4-phenyl-N-›4-(trifluoromethyl)benzyl!-3-isoquin
olinecarboxsmide
Melting point: 200.degree.-201.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.51 (3H, s), 4.35
(2H, d, J=5,8 Hz), 6.49 (1H, bt), 6.87 (2H, d, J=8.0 Hz), 7.16 (1H, d,
J=8.0 Hz), 7.30-7.56 (9H, m), 8.36 (1H, dd, J=7.9, 1.7 Hz)
EXAMPLE 172
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-1-oxo-4-phenyl-3-is
oquinolinecarboxamide
Melting point: 224.degree.-225.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.73 (3H, s), 7.20-7.70
(11H, m), 7.80 (1H, s), 8.53 (1H, d, J=8.4 Hz)
EXAMPLE 173
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-2-methyl-1-oxo-4-ph
enyl-3-isoquinolinecarboxamide
Melting point: 164.degree.-165.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.55 (3H, s), 4.34
(2H, d, J=6.0 Hz), 6.54 (1H, b), 7.08 (1H, m), 7.20-7.95 (6H, m), 7.52
(2H, s), 7.80 (2H, s), 8.28 (1H, d, J=8.6 Hz)
EXAMPLE 174
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-N,2-dimethyl-1-oxo-
4-phenyl-3-isoquinolinecarboxamide
Melting point: 165.degree.-166.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.77 (3H, s), 3.59
(3H, s), 4.25 (1H, d, J=14.6 Hz), 4.74 (1H, d, J=14.6 Hz), 7.10-7.60 (9H,
m), 7.80 (1H, s), 8.44 (1H, d, J=8.0 Hz)
EXAMPLE 175
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluoro-2-methylphenyl)-1,2-dihydro-
2-methyl-1-oxo-3-isoquinolinecarboxamide
Melting point: 189.degree.-190.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.02 (3H, s), 3.41
(3H, s), 4.33 (1H, dd, J=15.0, 5.4 Hz), 4.50 (1H, dd, J=15.0, 5.4 Hz),
6.65-6.95 (4H, m), 7.12 (1H, dd, J=8.4 Hz, 5.4 Hz), 7.48 (2H, m), 7.84
(1H, s), 8.34 (1H, d, J=7.6 Hz)
EXAMPLE 176
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluoro-2-methylphenyl)-1,2-dihydro-
N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide
Melting point: 142.degree.-143.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.11 (3H, s), 2.99
(3H, s), 3.58 (3H, s), 4.11 (1H, d, J=14.7 Hz), 4.97 (1H, d, J=14.7 Hz),
6.65 (1H, m), 6.80-7.63 (7H, m), 7.83 (1H, s), 8.51 (1H, m)
EXAMPLE 177
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-N-methyl-1-oxo-4-ph
enyl-3-isoquinolinecarboxamide
Melting point: 251.degree.-253.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.73 (3H, s), 4.0-5.0 (2H,
b), 7.33-7.56 (9H, m), 7.81 (1H, s), 8.35 (1H, d, J=8.4 Hz)
EXAMPLE 178
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2-dihydro-N-methyl-
1-oxo-3-isoquinolinecarboxamide
Melting point: 225.degree.-226.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.81 (3H, s),
4.1-5.1 (2H, b), 6.99-7.80 (9H, m), 7.83 (1H, s), 8.46 (1H, d, J=7.4 Hz)
EXAMPLE 179
N-›3,5-Bis(trifluoromethyl)benzyl!-2-(2-ethoxycarbonylethyl)-1,2-dihydro-1-
oxo-4-phenyl-3-isoquinolinecarboxamide
Melting point: 155.degree.-156.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 180
N-›3,5-Bis(trifluoromethyl)benzyl!-2-(2-ethoxycarbonylethyl)-1,2-dihydro-N-
methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide
A white powder
NMR (200 MHz, CDCl.sub.3) ppm: 1.26 (3H, t, J=7.0 Hz), 2.80 (3H, s), 2.97
(2H, t, J=7.2 Hz), 3.83 (1H, m), 4.00-4.27 (3H, m), 4.68 (1H, m), 4.48
(1H, d, J=14.2 Hz), 7.05-7.65 (10H, m), 7.80 (1H, s), 8.50 (1H, m)
EXAMPLE 181
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-1-oxo-4-(2-trifluor
omethylphenyl)-3-isoquinolinecarboxamide
Melting point: 176.5.degree.-177.5.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
EXAMPLE 182
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-(2-trif
luoromethylphenyl)-3-isoquinolinecarboxamide (C)
Melting point: 159.degree.-160.degree. C. (recrystaIlized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.89 (3H, s), 3.58
(3H, s), 4.11 (1H, d, J=14.6 Hz), 4.98 (1H, d, J=14.6 Hz), 6.86 (1H, m),
7.43 (2H, s), 7.46-7,56 (5H, m), 7.65 (1H, d, J=7.8 Hz), 7.78 (1H, s),
8.50 (1H, m)
EXAMPLE 183
N-›3,5-Bis(trifluoromethyl)benzyl!-2-›2-(N,N-dimethylamino)ethyl!-1,2-dihyd
ro-1-oxo-4-phenyl-3-isoquinolinecarboxamide
Melting point: 148.degree.-149.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 184
N-›3,5-Bis(trifluoromethyl)benzyl!-2-›2-(N,N-dimethylamino)ethyl!-1,2-dihyd
ro-N-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxamide hydrochloride
Melting point: 167.degree.-168.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.87 (3H, s), 2.92
(3H, s), 3.04 (3H, s), 3.23-3.52 (1H, b), 3.62-3.85 (1H, b), 3.99 (1H, d,
J=16.0 Hz), 4.30-4.60 (1H, b), 4.75-5.00 (1H, b), 5.66 (1H, d, J=16.0 Hz),
7.08-7.35 (6H, m), 7.42 (2H, s), 7.58 (2H, m), 7.77 (1H, s), 8.45 (1H, m)
EXAMPLE 185
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2,5,6,7,8-hexahydro-2-methyl-1-oxo-4-p
henyl-3-isoquinolinecarboxamide
Melting point: 224.degree.-225.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 186
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2,5,6,7,8-hexahydro-N,2-dimethyl-1-oxo
-4-phenyl-3-isoquinolinecarboxamide
Melting point: 200.degree.-201.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.40-2.70 (8H, m), 2.74
(3H, s), 3.50 (3H, s), 4.17 (1H, d, J=14.6 Hz), 4.73 (1H, d, J=14.4 Hz),
7.04 (1H, m), 7.22 (5H, m), 7.46 (2H, s), 7.78 (1H, m)
EXAMPLE 187
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-ethyl-2-methyl-1-oxo-4-phe
nyl-3-isoquinolinecarboxamide (C)
Melting point: 99.degree.-100.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.02 (3H, t, J=7.2 Hz),
2.95 (1H, m), 3.45 (1H, m), 3.61 (3H, s), 4.20 (1H, d, J=14.7 Hz), 4.87
(1H, d, J=14.7 Hz), 7.2-7.6 (10H, m), 7.78 (1H, s), 8.49-8.54 (1H, m)
EXAMPLE 188
N-›3,5-Bis(trifluoromethyl)benzyl!-5-fluoro-4-(4-fluorophenyl)-N,2-dimethyl
-1-oxo-3-isoquinolinecarboxamide
Melting point: 96.degree.-98.degree. C. (recrystallized from isopropyl
ether-ethyl acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.83 (3H, s), 3.57
(3H, s), 4.26 (1H, d, J=14.0 Hz), 4.67 (1H, d, J=14.6 Hz), 6.80-6.96 (2H,
m), 7.06-7.40 (2H, m), 7.42-7.54 (1H, m), 7.56 (2H, s), 7.83 (1H, d, J=1.2
Hz), 8.35 (1H, dd, J=1.0, 8.0 Hz)
EXAMPLE 189
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-ethyl-N-methyl-1-oxo-4-phe
nyl-3-isoquinolinecarboxamide
The compound obtained in Example 172 was reacted with ethyl iodide by a
method similar to Example 102(C) to yield the title compound.
Melting point: 105.degree.-106.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.39 (3H, t, J=7.0 Hz),
2.75 (3H, s), 3.85 (1H, m), 4.32 (1H, m), 4.45 (2H, s), 7.2-7.6 (10H, m),
7.80 (1H, s), 8.49-8.54 (1H, m)
EXAMPLE 190
1,2-Dihydro-N-(2-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoli
nemethylamine
To a solution of the compound (300 mg) obtained in Reference Example 52 in
THF (5 ml) was added 2-methoxybenzylamine (0.51 ml), followed by heating
at 130.degree. C. in a sealed tube for 2 hours. After ethyl acetate was
added, the reaction mixture was washed by successively with of aqueous
potassium carbonate and aqueous sodinrn chloride and then dried, after
which the solvent was distilled off. The residue was subjected to column
chromatography using silica gel (hexane:ethyl acetate=1:1) to yield the
title compound as colorless crystals (301 mg).
Melting point: 159.degree.-160.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.20 (3H, s), 2.36
(3H, s), 3.46 (2H, s), 3.64 (2H, s), 3.79 (3H, s), 3.82 (3H, s), 6.69 (1H,
s), 6.80 (1H, d, J=7.8 Hz) 6.84 (1H, d, J=6.0 Hz), 7.03 (1H, d, J=6.0 Hz),
7.12-7.30 (3H, m), 7.35-7.50 (3H, m), 8.22 (1H, s)
Elemental analysis (for C.sub.27 H.sub.28 N.sub.2 O.sub.2):
Calculated: C, 78.61; H, 6.84; N, 6.79
Found: C, 78.47; H, 6.88; N, 6.69
1(2H)-Isoquinoline derivatives having respective corresponding substituents
were reacted with amines in the same manner as in Example 190 to yield the
compounds of Example 191 to 206.
EXAMPLE 191
N-(3,5-Dimethylbenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquin
olinemethylamine
Melting point: 129.degree.-130.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.21 (3H, s), 2.27 (6H, s),
2.37 (3H, s), 3.48 (2H, s), 3.56 (2H, s), 3.82 (3H, s), 6.70 (1H, s), 6.79
(2H, s), 6.86 (1H, s), 7.15-7.30 (2H, m), 7.40-7.50 (3H, m), 8.24 (1H, s)
Elemental analysis (for C.sub.28 H.sub.30 N.sub.2 O):
Calculated: C, 81.91; H, 7.37; N, 6.82
Found: C, 82.05; H, 7.37; N, 6.82
EXAMPLE 192
N-(2-Chlorobenzyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquin
olinemethylamine
Melting point: 117.degree.-118.degree. C. (recrystallized from ethyl
ether-hexane)
EXAMPLE 193
N-(2-Chlorobenzyl)-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolin
emethylamine
Melting point: 141.degree.-142.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 194
1,2-Dihydro-N-›2-(2-methoxyphenyl)ethyl!-2,6,7-trimethyl-1-oxo-4-phenyl-3-i
soquinoline methylamine
Melting point: 119.degree.-120.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 195
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phen
yl-3-isoquinolinemethylamine hydrochloride
A white powder
NMR (200 MHz, DMSO-d.sub.6) ppm: 2.19 (3H, s), 2.36 (3H, s), 3.74 (3H, s),
4.05 (2H, bs), 4.14 (2H, bs), 6.63 (1H, s), 7.30-7.50 (5H, m), 8.12 (4H,
s), 9.94 (2H, bs)
Elemental analysis (for C.sub.28 H.sub.25 N.sub.2 OClF.sub.6):
Calculated: C, 60.60; H, 4.54; N, 5.05
Found: C, 60.78; H, 4.63; N, 4.78
EXAMPLE 196
1,2-Dihydro-N-(2-methoxybenzyl)-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoqui
nolinemethylamine
Melting point: 91.degree.-92.degree. C. (recrystallized from ethyl
ether-hexane)
EXAMPLE 197
1,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquirxolinemeth
ylamine
Melting point: 212.degree.-214.degree. C. (recrystallized from ethyl ethyl
acetate-ether)
EXAMPLE 198
1,2-Dihydro-N-(3-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethy
lamine
Melting point: 95.degree.-96.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 199
1,2-Dihydro-N-(4-methoxybenzyl)-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethy
lamide
Melting point: 94.degree.-95.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 200
N-›3,5-Bis(trifluoromethyl)phenyl!-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-is
oquinolinemethylamine
Melting point: 241.degree.-242.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 201
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-
3-isoquinolinemethylamine
Melting point: 135.degree.-136.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 202
1,2-Dihydro-2-methyl-1-oxo-4-phenyl-N-(2-pyridyl)methyl-3-isoquinolinemethy
lamine
Melting point: 145.degree.-146.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 203
1,2-Dihydro-N-(2-methoxybenzyl)-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquin
olinemethylamine
Melting point: 91.degree.-92.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 204
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-methyl-4-(2-methylphenyl)-
1-oxo-3-isoquinolinemethylamine hydrochloride
A white powder
NMR (200 MHz, DMSO-d.sub.6) ppm: 1.95 (3H, s), 3.77 (3H, s), 3.50-4.50 (4H,
m), 6.70-6.85 (1H, m), 7.20-7.45 (4H, m), 7.50-7.70 (2H, m), 8.07 (3H, s),
8.30-8.40 (1H, m), 9.60-10.60 (1H, m)
EXAMPLE 205
1,2-Dihydro-2-methyl-1-oxo-4-phenyl-N-(3,4,5-trimethoxybenzyl)-3-isoquinoli
nemethylamine
Melting point: 131.degree.-132.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.54 (2H, s), 3.59
(2H, s), 3.82 (9H, s), 3.86 (3H, s), 6.45 (2H, s), 6.96 (1H, m), 7.20-7.28
(2H, m), 7.42-7.50 (5H, m), 8.49 (1H, m)
EXAMPLE 206
4-(2-Ethylphenyl)-1,2-dihydro-N-(2-methoxybenzyl)-2-methyl-1-oxo-3-isoquino
linemethylamine hydrochloride
A white powder
NMR (200 MHz, CDCl.sub.3) ppm: 0.98 (3H; t, J=7.5 Hz), 2.30 (2H, q, J=7.5
Hz), 3.40 (1H, d, J=13Hz), 3.49 (1H, d, J=13 Hz), 3.65 (2H, s), 3.78 (3H,
s), 3.85 (3H, s), 6.73-6.88 (3H, m), 7.00-7.29 (4H, m), 7.33-7.48 (4H, m),
8.48 (1H, m)
EXAMPLE 207
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl
2-(2-methoxyphenyl)ethyl ether
A mixture of 2-methoxyphenethyl alcohol (0.125 ml), sodium hydride (60% in
oil) (50 mg) and DMF (5 ml) was stirred at room temperature for 30
minutes. After this mixture was cooled to 0.degree. C., the compound (200
mg) obtained in Reference Example 52 was added, followed by stirring at
room temperature for 30 minutes. After dilute hydrochloric acid was added,
the mixture was extracted with ethyl acetate. The extract was washed with
aqueous potassium carbonate and water and then dried, after which the
solvent was distilled off. The residue was subjected to column
chromatography using silica gel (hexane:ethyl acetate=3:2) to yield the
title compound as colorless crystals (101 mg).
Melting point: 114.degree.-115.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.22 (3H, s), 2.38
(3H, s), 2.83 (2H, t, J=7.0 Hz), 3.53 (2H, t, J=7.0 Hz), 3.67 (3H, s),
3.76 (3H, s), 4.22 (2H, s), 6.78-6.92 (3H, m), 7.05-7.30 (4H, m),
7.38-7.50 (3H, m), 8.25 (1H, s)
Elemental analysis (for C.sub.28 H.sub.29 NO.sub.3):
Calculated: C, 78.66; H, 6.84; N, 3.28
Found: C, 78.60; H, 6.91; N, 3.19
1(2H)-Isoquinolinone derivatives having respective corresponding
substituents were reacted with alcohols in the same manner as in Example
207 to yield the compounds of Examples 208 to 216.
EXAMPLE 208
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl
3,5-dimethylbenzyl ether
Melting point: 99.degree.-100.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.23 (3H, s), 2.28
(6H, s), 2.38 (3H, s), 3.78 (3H, s), 4.28 (2H, s), 4.30 (2H, s), 6.81 (1H,
s), 6.84 (2H, s), 6.91 (1H, s), 7.25-7.35 (2H, m), 7.40-7.50 (3H, m), 8.26
(1H, s)
Elemental analysis (for C.sub.28 H.sub.29 NO.sub.2):
Calculated: C, 81.72; H, 7.10; N; 3.40
Found: C, 81.64; H, 7.29; N, 3.25
EXAMPLE 209
Benzyl 1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoline-methyl
ether
Melting point: 127.degree.-128.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 210
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl
2-methoxybenzyl ether
Melting point: 105.degree.-106.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 211
3,5-Bis(trifluoromethyl)benzyl
1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethyl ether
Melting point: 133.degree.-134.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.83 (3H, s), 4.42
(2H, s), 4.48 (2H, s), 7.00-7.10 (1H, m), 7.20-7.30 (2H, m), 7.35-7.60
(5H, m), 7.67 (2H, s), 7.79 (1H, s), 8.45-8.60 (1H, m)
EXAMPLE 212
3,5-Bis(trifluoromethyl)benzyl
1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinoline methyl ether
A colorless oily substance
NMR (200 MHz, CDCl.sub.3) ppm: 2.02 (3H, s), 3.85 (3H, s), 4.28 (1H, d,
J=12 Hz), 4.45 (1H, d, J=12 Hz), 4.48 (2H, s), 6.85-7.00 (1H, m),
7.10-7.35 (4H, m), 7.45-7.55 (2H, m), 7.66 (2H, s), 7.79 (1H, s),
8.50-8.60 (1H, m)
EXAMPLE 213
1,2-Dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinemethyl
2-(2-methoxyphenyl)ethyl ether
Melting point: 145.degree.-147.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.83 (2H, t, J=6.8
Hz), 3.54 (2H, t, J=6.8 Hz), 3.68 (3H, s), 3.75 (3H, s), 4.25 (2H, s),
6.78-6.92 (2H, m), 7.04-7.30 (5H, m), 7.38-7.52 (5H, m), 8.46-8.54 (1H, m)
EXAMPLE 214
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinemethyl
4-methoxybenzyl ether
Melting point: 123.degree.-124.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 215
2-(1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline-3-yl)ethyl-3,5-di
methylbenzyl ether
Melting point: 150.degree.-151.degree. C. (recrystallized from
ethylether-hexane)
EXAMPLE 216
3,5-Bis(trifluoromethyl)benzyl
4-(2-ethylphenyl)-1,2-dihydro-2-methyl-1-oxo-3-isoquinolinemethyl ether
A colorless oil
NMR (200 MHz, CDCl.sub.3) ppm: 0.99 (3H, t, J=7.7 Hz), 2.34 (2H, q, J=7.7
Hz), 3.82 (3H, s), 4.27 (1H, d, J=12 Hz), 4.45 (1H, d, J=12 Hz), 4.48 (2H,
s), 6.93 (1H, m), 7.10-7.57 (6H, m), 7.67 (2H, s), 7.79 (1H, s), 8.51 (1H,
m)
EXAMPLE 217
3,5-Bis(trifluoromethyl)benzyl
1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinemethyl sulfide
The compound obtained in Reference Example 68 was reacted with
3,5-bis(trifluoromethyl)benzyl bromide in DMF in the presence of sodinto
hydride by a method similar to Example 207 to yield the title compound as
colorless crystals.
Melting point: 178.degree.-179.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 218
3,5-Bis(trifluoromethyl)benzyl
1,2-dihydro-2-methyl-4-(2-methylphenyl)-1-oxo-3-isoquinolinemethyl
sulfoxide
A mixture of the compound obtained in Reference Example 217,
m-chloroperbenzoic acid (purity 70%) (50 mg) and dichloromethane (20 ml)
was stirred for 30 minutes with ice cooling. After evaporation of the
solvent, the residue was dissolved in ethyl acetate, washed successively
with water, diluted hydrochloric acid and aqueous sodium hydrogen
carbonate, dried and evaporated. The residue was subjected to silica gel
column chromatography (ethyl acetate) to yield the title compound as
colorless crystals (60.3 mg).
Melting point: 173.degree.-174.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.97, 2.00 (total
3H, each s), 3.65-3.95 (4H, m), 3.80, 3.81 (total 3H, each s), 6.83 (1H,
m), 7.10 (1H, m), 7.19-7.35 (3H, m), 7.45-7.55 (4H, m), 7.84 (1H, s), 8.50
(1H, m)
EXAMPLE 219
N-Benzyl-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetamide
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetic acid
(Reference Example 56) and benzylamine were reacted (amidation) and
treated in substantially the same manner as in Example 101 to yield the
title compound as colorless crystals.
Melting point: 222-222.5.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.19 (3H, s), 2.34
(3H, s), 3.54 (2H, s), 3.66 (3H, s), 4.41 (2H, d, J=6.0 Hz), 5.87 (1H,
bt), 6.68 (1H, s), 7.10-7.45 (10H, m), 8.18 (1H, s)
Elemental analysis (for C.sub.27 H.sub.26 N.sub.2 O.sub.2
.multidot.0.1H.sub.2 O):
Calculated: C, 78.65; H, 6.40; N, 6.79
Found: C, 78.46; H, 6.40; N, 6.94
Isoquinolineacetic acid derivatives having respective corresponding
substituents were reacted with amines in the same manner as in Example 219
to yield the compounds of Example 220 to 223.
EXAMPLE 220
1,2-Dihydro-N-(4-methoxybenzyl)-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoli
neacetamide
Melting point: 214.degree.-215.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 221
N-(2-Chlorobenzyl)-1,2-dihydro-N,2,6,7-tetramethyl-1-oxo-4-phenyl-3-isoquin
olineacetamide
Melting point: 191.degree.-192.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 222
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-1,2-dihydro-N,2-dimethyl-1-oxo-
4-phenyl-3-isoquinolineacetamide
Melting point: 156.degree.-157.degree. C. (recrystallized from ethyl
acetate-hexane)
EXAMPLE 223
N-›3,5-Bis(trifluoromethyl)phenyl!-6-chloro-1,2-dihydro-2-methyl-1-oxo-4-ph
enyl-3-isoquinolineacetamide
Melting point: 288.degree.-289.degree. C. (recrystallized from
methanol-ethyl acetate)
EXAMPLE 224
N-›3,5
-Bis(trifluoromethyl)phenyl!-1,2-dihydro-N,2-dimethyl-1-oxo-4-phenyl-3-iso
quinolineacetamide
A mixture of the compound obtained in Example 222 (250 mg), methanol (8
ml), THF (2 ml), 10% palladium-carbon (50% hydrated) (130 mg) and sodium
acetate (60 mg) was stirred in a hydrogen atmosphere for 1 hour at room
temperature. The catalyst was filtered off, and the filtrate was
evaporated. The residue was dissolved in ethyl acetate, washed with water,
dried and evaporated to yield the title compound as colorless crystals
(160 mg).
Melting point: 193.degree.-194.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 225
N-›3,5-Bis(trifluoromethyl)benzyl!-2-carbamoylmethyl-1,2-dihydro-6,7-dimeth
yl-1-oxo-4-phenyl-3- isoquinolinecarboxamide
To a solution of the compound (190 mg) obtained in Reference Example 59 in
dichloromethane (10 ml) were added oxalyl chloride (0.052 ml) and DMF (one
drop), followed by stirring at room temperature for 1 hour. After the
solvent was distilled off, the residue was dissolved in dichloromethane
(10 ml). To this solution was added a solution of
3,5-bis(trifluoromethyl)benzylamine (170 mg) and triethylamine (0.077 ml)
in dichloromethane (5 ml), followed by stirring at room temperature for 5
hours. After the solvent was distilled off, ethyl acetate was added to the
residue. This mixture was washed successively with water, dilute
hydrochloric acid, water, aqueous sodium hydrogen carbonate and water and
then dried, after which the solvent was distilled off. The residue was
dissolved in methanol (5 ml), and 15% ammonia-methanol (10 ml) was added
at room temperature, followed by stirring for 15 hours and then solvent
removal by distillation, to yield the title compound as colorless crystals
(125 mg).
Melting point: 235.degree.-237.degree. C. (recrystallized from methanol)
Elemental analysis (for C.sub.29 H.sub.23 N.sub.3 O.sub.3 F.sub.6):
Calculated: C, 60.52; H, 4.03; N, 7.30
Found: C, 60.72; H, 4.11; N, 7.52
The compound obtained in Reference Example 59 and benzylamines having
respective corresponding substituents were reacted and treated in the same
manner as in Example 225 to yield the compounds of Examples 226 and 227.
EXAMPLE 226
2-Carbamoylmethyl-1,2-dihydro-6,7-dimethyl-N-(3,5-dimethylbenzyl)-1-oxo-4-p
henyl-3-isoquinolinecarboxamide
Melting point: 253.degree.-254.degree. C. (recrystallized from ethanol)
EXAMPLE 227
2-Carbamoylmethyl-1,2-dihydro-N-(2-methoxybenzyl)-6,7-dimethyl-1-oxo-4-phen
yl-3-isoquinolinecarboxamide
Melting point: 234.5.degree.-236.degree. C. (recrystallized from ethanol)
EXAMPLE 228
1,2,3,4-Tetrahydro-2-(2-methoxybenzyl)-8,9-dimethyl-3,6-dioxo-11-phenyl-6H-
pyrazino›1,2-b!isoquinoline
To a solution of
2-ethoxycarbonylmethyl-1,2-dihydro-3-hydroxymethyl-6,7-dimethyl-1-oxo-4-ph
enylisoquinoline (Reference Example 51) (183 mg) in dichloromethane (10 ml)
were added methanesulfonyl chloride (0.037 ml) and triethylamine (0.084
ml) with ice cooling, followed by stirring for 30 minutes. The reaction
mixture was poured into water and extracted with dichloromethane. The
extract was washed with water and then dried, after which the solvent was
distilled off. The residue was mixed with 2-methoxybenzylamine (0.196 ml)
and THF (5 ml), followed by heating at 130.degree. C. in a sealed tube for
3 hours. The reaction mixture was poured into aqueous sodium hydrogen
carbonate and extracted with ethyl acetate. The extract was washed with
water and then dried, after which the solvent was distilled off. The
residue was subjected to silica gel column chromatography
(hexane:acetone=1:1) to yield the title compound as colorless crystals
(110 mg).
Melting point: 211.degree.-214.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.22 (3H, s), 2.37 (3H, s),
3.54 (3H, s), 4.15 (2H, s), 4.60 (2H, s), 4.88 (2H, s), 6.76-6.98 (5H, m),
7.13-7.28 (2H, m), 7.36-7.42 (3H, m), 8.23 (1H, s)
Elemental analysis (for C.sub.28 H.sub.26 N.sub.2 O.sub.3):
Calculated: C, 76.67; H, 5.97; N, 6.39
Found: C, 76.41; H, 6.05; N, 6.40
EXAMPLE 229
1,2,3,4-Tetrahydro-1-(4-methoxybenzyloxy)-8,9-dimethyl-6-oxo-11-phenyl-6H-b
enzo›b!quinolizine
To a solution of the compound (160 mg) obtained in Reference Example 65 in
DMF (5 ml) was added sodium hydride (60% in oil) (22 mg), followed by
stirring at room temperature for 15 minutes. While ice cooling the
solution, 4-methoxybenzyl chloride (0.075 ml) was added, followed by
stirring at room temperature for 4 hours. The reaction mixture was poured
into water and extracted with ethyl acetate. The extract was washed
successively with dilute hydrochloric acid, water, aqueous sodium hydrogen
carbonate and water and then dried, after which the solvent was distilled
off. The residue was subjected to silica gel column chromatography
(hexane:ethyl acetate=5:1) to yield the title compound as colorless
crystals (170 mg).
Melting point: 145.degree.-146.degree. C. (recrystallized from ethyl
ether-hexane)
Elemental analysis (for C.sub.29 H.sub.29 NO.sub.3):
Calculated: C, 79.24; H, 6.65; N, 3.19
Found: C, 79.30; H, 6.85; N, 3.14
The compound obtained in Reference Example 65 and benzyl chlorides having
respective corresponding substituents were reacted (alkylation) and
treated in the same manner as in Example 229 to yield the compounds of
Examples 230 to 232
EXAMPLE 230
1-Benzyloxy-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6H-benzo›b!quin
olizine
Melting point: 133.degree.-134.degree. C. (recrystallized from ethyl
ether-hexane)
EXAMPLE 231
1-(3,5-Dimethylbenzyloxy)-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6
H-benzo›b!quinolizine
Melting point: 146.degree.-147.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 232
1,2,3,4-Tetrahydro-1-(2-methoxybenzyloxy)-8,9-dimethyl-6-oxo-11-phenyl-6H-b
enzo›b!quinolizine
Melting point: 186.degree.-188.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 233
1-(3,5-Dimethylbenzylamino)-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl
-6H-benzo›b!quinolizine hydrochloride
A mixture of the compound (159 mg) obtained in Reference Example 64, acetic
acid (0.03 ml), 3,5-dimethylbenzaldehyde (0.1 ml) and methanol (10 ml) was
stirred at room temperature for 15 minutes. After sodium cyanoborohydride
(60 mg) was added, the mixture was stirred at room temperature for 30
minutes. After the solvent was distilled off, aqueous sodium hydrogen
carbonate was added, and the mixture was extracted with ethyl acetate. The
extract was washed with water and then dried, after which the solvent was
distilled off, to yield the free form of the title compound as a colorless
oily substance. This compound was dissolved in ether (1 ml), and 4N
HCl-ethyl acetate (3 ml) was added while ice cooling the solution,
followed by solvent removal by distillation, to yield the title compound
as colorless crystals (160 mg).
Melting point: 205.degree.-208.degree. C. (recrystallized from ethanol) NMR
(200 MHz, CDCl.sub.3) ppm: ›free base!
1.55-2.05 (4H, m), 2.22 (3H, s), 2.25 (6H, s), 2.36 (3H, s), 3.20 (1H, d,
J=12.4 Hz), 3.40 (1H, d, J=12.4 Hz), 3.91 (1H, bs), 4.30 (1H, m), 4.59
(1H, m), 6.70 (2H, s), 6.74 (1H, s), 6.83 (1H, s), 7.21-7.32 (2H, m), 7.48
(3H, m), 8.24 (1H, s)
Elemental analysis (for C.sub.30 H.sub.32 N.sub.2
O.multidot.HCl.multidot.0.2H.sub.2 O):
Calculated: C, 75.59; H, 7.06; N, 5.88
Found: C, 75.42; H, 7.29; N, 5.72
EXAMPLE 234
1,2,3,4-Tetrahydro-8,9-dimethyl-1-›N-methyl-(3,5-dimethylbenzyl)amino!-6-ox
o-11-phenyl-6H-benzo›b!quinolizine
The compound obtained in Example 233 and formalin were reacted and treated
with sodium borohydride in the same manner as in Example 233 to yield the
title compound as colorless crystals.
Melting point: 144.degree.-145.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Amine compounds having respective corresponding substituents and aldehydes
were reacted and treated with sodium borohydride in the same manner as in
Examples 233 and 234 to yield the compounds of Example 235 to 239 (free
form or hydrochloride).
EXAMPLE 235
1-›3,5-Bis(trifluoromethyl)benzylamino!-1,2,3,4-tetrahydro-8,9-dimethyl-6-o
xo-11-phenyl-6H-benzo›b!quinolizine
Melting point: 189.5.degree.-191.5.degree. C. (recrystallized from
isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.70-2.00 (4H, m), 2.22
(3H, s), 2.38 (3H, s), 3.36 (1H, d, J=13.4 Hz), 3.56 (1H, d, J=13.4 Hz),
3.94 (1H, bs), 4.27 (1H, m), 4.56 (1H, m), 6.74 (1H, s), 7.25 (2H, m),
7.47 (3H, m), 7.57 (2H, s), 7.71 (1H, s), 8.25 (1H, s)
Elemental analysis (for C.sub.30 H.sub.26 N.sub.2 OF.sub.6):
Calculated: C, 66.17; H, 4.81; N, 5.14
Found: C, 65.88; H, 4.79; N, 5.01
EXAMPLE 236
1,2,3,4-Tetrahydro-8,9-dimethyl-1-›N-methyl-›3,5-bis(trifluoromethyl)
benzyl!amino!-6-oxo-11-phenyl-6H-benzo›b!quinolizine hydrochloride
Melting point: 116.degree.-119.degree. C. (recrystallized from ethanol)
EXAMPLE 237
1-(2-Chlorobenzylamino)-1,2,3,4-tetrahydro-8,9-dimethyl-6-oxo-11-phenyl-6H-
benzo›b!quinolizine hydrochloride
Melting point: 201.degree.-204.degree. C. (recrystallized From ethanol)
EXAMPLE 238
1,2,8,4-Tetrahydro-1-(2-methoxybenzylamino)-8,9-dimethyl-6-oxo-11-phenyl-6H
-benzo›b!quinolizine hydrochloride
Melting point: 211.degree.-215.degree. C. (recrystallized from
methanol-ethanol)
EXAMPLE 289
1,2,3,4-Tetrahydro-1-(2-methoxybenzylamino)-6-oxo-11-phenyl-6H-benzo›b!quin
olizine
Melting point: 135.degree.-137.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 240
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6
H-pyrazino›1,2-b!isoquinoline
A solution of the compound obtained in Reference Example 66 (103 mg) in DMF
(5 ml) was added sodium hydride (60% in oil) (16 mg), and the mixture was
stirred for 30 minutes at room temperature, followed by addition of
3,5-bis(trifluoromethyl)benzyl bromide (74 .mu.l) with ice cooling and the
mixture was stirred for 1 hour at room temperature. Water was added to the
mixture, which was extracted with ethyl acetate. The extract was washed
with water, dried and evaporated to yield the title compound as colorless
crystals (65 mg).
Melting point: 204.degree.-206.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.63 (2H, m), 4.44
(2H, m), 4.78 (2H, s), 7.18-7.27 (3H, m), 7.44-7.66 (5H, m), 7.68 (2H, s),
7.82 (2H, s), 8.52 (1H, m)
EXAMPLE 241
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6
H-pyrazino›1,2-b!isoquinoline
A solution of the compound obtained in Reference Example 67 (140 mg) in DMF
(5 ml) were added potassium carbonate (76 mg) and
3,5-bis(trifluoromethyl)benzyl bromide (111 .mu.l), and the mixture was
stirred for 30 minutes at 70.degree.-80.degree. C. Water was added to the
mixture, which was extracted with ethyl acetate. The extract was washed
with water, dried and evaporated to yield the title compound as colorless
crystals (170 mg).
Melting point: 194.degree.-196.degree. C. (recrystallized from ethyl
acetate)
EXAMPLE 242
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-1-oxo-4-phenyl-1H-2-be
nzopyran-3-carboxamide
6-Chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid was reacted with
N-›3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar to
Example 101 (amidation) to yield the title compound.
Melting point: 170.degree.-171.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.78 (3/5H, s), 2.91
(3.times.4/5H, s), 4.59 (2H, s), 7.18 (1H, s), 7.27-7.57 (8H, m), 7.80
(1H, s), 8.33 (1H, d, J=8.6 Hz)
The compounds of Example 243-247 were obtained from the
1-oxo-1H-2-benzopyran-3-carboxylic acids and amines, which have
substituents corresponding to each Example, by a method similar to Example
242 (amidation).
EXAMPLE 243
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-1-oxo-4-phenyl-1H-2-benzopyran-
3-carboxamide
Melting point: 151.degree.-152.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.78 (3/5H, s), 2.92
(3.times.4/5H, s), 4.60 (2H, s), 7.22-7.75 (10H, m), 7.80 (1H, s),
8.39-8.43 (1H, m)
EXAMPLE 244
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(2-methoxyphenyl)-N-methyl-1-oxo-1H-2-
benzopyran-3-carboxamide
Melting point: 153.degree.-154.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.91 (3/4H, s), 3.06
(3.times.3/4H, s), 3.56 (3/4H, s), 3.74 (3.times.3/4H, s), 4.42 (1H, d,
J=14.6 Hz), 5.01 (1H, d, J=14.6 Hz), 6.95-7.80 (9H, m), 7.91 (1H, s),
8.48-8.53 (1H, m)
EXAMPLE 245
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1-oxo-1H-2-benzopyran
-3-carboxamide
Melting point: 166.degree.-167.degree. C. (recrystallized from ethyl ether)
EXAMPLE 246
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-N-methyl-1-oxo-1H-2-b
enzopyran-3-carboximide
Melting point: 132.degree.-133.degree. C. (recrystallized from ethyl
ether-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.96 (3H, s), 4.61
(2H, s), 7.08 (1H, d, J=8.6 Hz), 7.13-7.22 (2H, m), 7.30 (1H, dd, J=7.2,
3.6 Hz), 7.32 (1H, m), 7.52 (2H, s), 7.58-7.76 (2H, m), 7.82 (1H, s), 8.41
(1H, dd, J=7.2, 1.2 Hz)
EXAMPLE 247
N-›3,5-Bis(trifluoromethyl)benzyl!-N,6-dimethyl-1-oxo-4-phenyl-1H-2-benzopy
ran-3-carboxmamide
Melting point: 162.degree.-163.degree. C. (recrystallized from isopropyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.38, 2.39 (total 3H, each
s), 2.77 (1/4.times.3H, s), 2.91 (3/4.times.3H, s), 4.58 (2H, s), 6.99
(1H, s), 7.25-7.42 (6H, m), 7.49 (2H, s), 7.78 (1H, s), 8.29 (1H, d, J=8.0
Hz)
EXAMPLE 248
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-4-(2-methylphenyl)-2-o
xo-4H-1-benzopyran-3-carboxamide
6-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid was
reacted with N-›3,5-bis(trifluoromethyl)benzyl!methylamine by a method
similar to Example 101 (amidation) to yield the title compound.
Melting point: 148.degree.-149.degree. C. (recrystalized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.08 (1H, s), 2.20 (2H, s),
2.86 (1H, s), 3.00 (2H, s), 4.37 (1H, d, J=15.2 Hz), 4.88 (2/3H, d, J=15.2
Hz), 4.92 (1/3H, d, J=15.2 Hz), 6.89-7.56 (9H, m), 7.76 (1H, s)
The compounds of Example 249-253 were obtained from the
2-oxo-2H-1-benzopyran-3-carboxylic acids and amines, which have
substituents corresponding to each Example, by a method similar to Example
248 (amidation).
EXAMPLE 249
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-2-oxo-4-phenyl-2H-1-be
nzopyran-3-carboxamide
Melting point: 172.degree.-173.degree. C. (recrystalized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.74 (0.57H, s),
2.85 (2.43H, s), 4.18 (0.19H, d, J=15.6 Hz), 4.40 (0.81H, d, J=15.4 Hz),
4.63 (0.19H, d, J=16.2 Hz), 4.88 (0.81H, d, J=15.0 Hz), 7.12-7.70 (10H,
m), 7.78 (1H, s)
EXAMPLE 250
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-oxo-4-phenyl-2H-1-benzopyran-
3-carboxamide
Melting point: 146.degree.-147.degree. C. (recrystallized from ethyl
acetate hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.74 (3/5H, s), 2.86
(3.times.4/5H, s), 4.22 (1/5H, d, J=15.6 Hz), 4.39 (4/5H, d, J=15.2 Hz),
4.69 (1/5H, d, J=15.6 Hz), 4.91 (4/5H, d, J=15.2 Hz), 7.14-7.70 (11H, m),
7.78 (1H, s)
EXAMPLE 251
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-4-(2-methoxyphenyl)-N-methyl-2-
oxo-2H-1-benzopyran-3-carboxamide
Melting point: 121.degree.-122.degree. C. (recrystallized from isopropyl
ether-ethyl acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.85 (3H, s), 3.63
(3H, s), 4.29 (1H, d, J=15.4 Hz), 4.98 (1H, d, J=15.0 Hz), 6.90-7.09 (3H,
m), 7.30-7.64 (6H, m), 7.77 (1H, s)
EXAMPLE 252
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-2-oxo-4-(2-trifluorome
thylphenyl)-2H-1-benzopyran-3-carboxamide
Melting point: 206.degree.-207.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.92 (3H, s), 4.33 (1H, d, J=15.2
Hz), 4.92 (1H, d, J=15.4Hz), 6.77 (1H, d, J=2.2 Hz), 7.38 (1H, d, J=8.8
Hz), 7.46-7.58 (3H, m), 7.60-7.88 (5H, m)
EXAMPLE 253
6-Chloro-N-(2,6-dimethoxybenzyl)-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3
-carboxamide
Melting point: 190.degree.-191.degree. C. (recrystallized from ethanol)
EXAMPLE 254
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-(2-methylphenyl)-2-oxo-2H-
1-benzopyran-3-carboxamide
The compound obtained in Reference 248 was reacted by a method similar to
Example 224 (catalytic reduction) to yield the title compound.
Melting point: 130.degree.-13 1.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.07 (1H, s), 2.22 (2H, s),
2.87 (1H, s), 3.01 (2H, s), 4.36 (1H, d, J=15.2 Hz), 4.90 (2/3H, d, J=15.2
Hz), 4.95 (1/3H, d, J=15.2 Hz), 6.92-7.57 (10H, m), 7.76 (1H, s)
The compounds of Example 255 and 256 were obtained from the compounds of
Example 251 and 252, respectively, by a method similar to Example 254
EXAMPLE 255
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(2-methoxyphenyl)-N-methyl-2-oxo-2H-1-
benzopyran-3-carboxamide
Melting point: 140.degree.-142.degree. C. (recrystallized from isopropyl
ether-ethyl acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.87 (3H, s), 3.61
(3H, s), 4.28 (1H, d, J=15.2 Hz), 5.01 (1H, d, J=15.2 Hz), 6.85-7.22 (4H,
m), 7.30-7.62 (6H, m), 7.77 (1H, s)
EXAMPLE 256
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-oxo-4-(2-trifluoromethylpheny
l)-2H-1-benzopyran-3-carboxamide
Melting point: 135.degree.-137.degree. C. (recrystallized from isopropyl
ether-ethyl acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.94 (3H, s), 4.33
(1H, d, J=15.4 Hz), 4.95 (1H, d, J=15.0 Hz), 6.84 (1H, dd, J=1.4, 8.0 Hz),
7.20 (1H, dt, J=1.4, 7.2 Hz), 7.43 (1H, dd, J=1.0, 8.4 Hz), 7.52-7.82 (8H,
m)
EXAMPLE 257
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-2-oxo-4-phenyl-3-quinolineca
rboxamide
1,2-Dihydro-2-oxo-4-phenyl-3-quinolinecarboxylic acid was reacted with
3,5-bis(trifluoromethyl)benzylamine by a method similar to Example 101
(amidation) to yield the title compound.
Melting point: 251.degree.-252.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
The compounds of Example 258-263 were obtained from the
1,2-dihydro-2-oxo-3-quinolinecarboxylic acids and amines, which have
substituents corresponding to each Example, by a method sirnilar to
Example 257 (amidation).
EXAMPLE 258
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-2-oxo-4-phenyl-3-qu
inolinecarboxamide
Melting point: 262.degree.-264.degree. C. (recrystallized from ethyl
acetate hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.87 (3H, s), 4.61 (1H, d,
J=15 Hz), 4.75 (1H, d, J=15 Hz), 7.10-7.60 (9H, m), 7.66 (2H, s), 7.78
(1H, s), 12.44 (1H, bs)
EXAMPLE 259
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-qu
inolinecarboxamide
Melting point: 191.degree.-192.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 260
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,1-dimethyl-2-oxo-4-phenyl-
3-quinolinecarboxamide
Melting point: 163.degree.-164.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.83 (3H, s), 3.83 (3H, s),
4.29 (1H, d, J=15 Hz), 5.00 (1H, d, J=15 Hz), 7.16 (2H, m), 7.24-7.70 (9H,
m), 7.75 (1H, s)
EXAMPLE 261
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-
2-oxo-3-quinolinecarboxamide
A white form
NMR (200 MHz, CDCl.sub.3) ppm: 3.87 (3H, s), 4.54 (1H, dd, J=16, 5.6 Hz),
4.69 (1H, dd, J=16, 6.5 Hz), 7.05-7.53 (7H, m), 7.68 (1H, m), 7.69 (2H,
s), 7.73 (1H, s), 9.17 (1H, bs)
EXAMPLE 262
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-N,1-dimet
hyl-2-oxo-3-quinolinecarboxamide
Melting point: 189.degree.-190.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.94 (3H, s), 3.84 (3H, s),
4.25 (1H, d, J=15 Hz), 5.08 (1H, d, J=15 Hz), 7.03-7.23 (2H, m), 7.32-7.65
(8H, m), 7.75 (1H, s)
EXAMPLE 263
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(2-chlorophenyl)-1,2-dihydro-N,1,6-tri
methyl-2-oxo-3-quinolinecarboxamide
Melting point: 226.degree.-227.degree. C. (recrystallized from ethyl
acetate-isorpropyl ether)
EXAMPLE 264
N-›3,5-Bis(trifluoromethyl)benzyl!-6-chloro-N-methyl-4-phenyl-3-quinolineca
rboxamide
6-Chloro-4-phenylquinoline-3-carboxylic acid was reacted with
N-›3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar to
Example 101 (amidation) to yield the title compound.
Melting point: 105.degree.-106.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.60 (3.times.4/5H, s),
2.81 (3/5H, s), 4.0-5.2 (2H, b), 7.29-7.81 (10H, m), 8.16 (1H, d, J=8.8
Hz), 8.91 (1H, s)
EXAMPLE 265
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-phenyl-3-quinolinecarboxamide
The compound obtained in Example 264 was reacted by a method similar to
Example 224 (catalytic reduction) to yield the title compound.
Melting point: 96.degree.-97.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.61 (3.times.6/7H, s),
2.81 (3/7H, s), 4.0-5.2 (2H, b), 7.28-7.83 (11H, m), 8.22 (1H, d, J=8.8
Hz), 8.93 (1H, s)
The compounds of Example 266-268 were obtained from the
quinoline-3-carboxylic acids and amines, which have substituents
corresponding to each Example, by a method similar to Example 264
(amidation)
EXAMPLE 266
N-›3,5-Bis(trifluorornethyl)benzyl!-2-methyl-4-phenyl-3-quinolinecarboxamid
e
Melting point: 191.degree.-192.degree. C. (recrystallized from ethyl
ether-hexane)
EXAMPLE 267
N-›3,5-Bis(trifluoromethyl)benzyl!-N,2-dimethyl-4-phenyl-3-quinolinecarboxa
mide
Melting point: 146.degree.-147.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.61 (3H, s), 2.74 (3H, s),
4.42 (1H, d, J=15 Hz), 4.77 (1H, d, J=15 Hz), 7.20-7.85 (11H, m), 8.09
(1H, d, J=8.8 Hz)
EXAMPLE 268
N-›3,5-Bis(trifluororaethyl)benzyl!-2,6,7-trimethoxy-N-raethyl-4-phenyl-3-q
uinolinecarboxamide
Melting point: 88.degree.-89.degree. C. (recrystallized from isorpopyl
ether-hexane)
EXAMPLE 269
N-›3,5-Bis(trifluororaethyl)benzyl!-2-chloro-N-methyl-4-phenyl-3-quinolinec
arboxamide
A mixture of the compound obtained in Example 258 (2.55 g) and phosphorus
oxychloride (60 ml) was stirred for 2 hours with heating under reflux. The
solvent was evaporated and the residue was dissolved in ethyl acetate. The
solution was washed with cooled aqueous sodium hydrogen carbonate and
water, dried and evaporated to yield the title compound as colorless
crystals (2.45 g).
Melting point: 147.degree.-148.degree. C. (recrystallized from ether
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.71 (3H, s), 4.54
(1H, d, J=14.9 Hz), 4.71 (1H, d, J=14.9 Hz), 7.20-8.13 (h, m), 8.11 (1H,
d, J=8.4 Hz)
EXAMPLE 270
N-›3,5-Bis(trifluororaethyl)benzyl!-2-methoxy-N-methyl-4-phenyl-3-quinoline
carboxamide
To a solution of the compound obtained in Example 269 (100 mg) in methanol
(2 ml) was added 28% NaOMe-methanol (2 ml), and the mixture was stirred
for 3 hours with heating under reflux. The solvent was evaporated and the
residue was dissolved in ethyl acetate. The solution was washed with
water, dried and evaporated to yield the title compound as colorless
crystals (85 mg).
Melting point: 146.degree.-147.degree. C. (recrystallized frora ether
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.70 (2H, s), 2.72 (1H, s),
3.82 (1/3H, d, J=15.7 Hz), 4.15 (1H, s), 4.18 (2H, s), 4.39 (2/3H, d, J=15
Hz), 4.62 (1/3H, d, J=15.7 Hz), 4.89 (2/3H, d, J=15.6 Hz), 17.7-7.95 (12H,
m)
EXAMPLE 271
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-methylamino-4-phenyl-3-quinol
inecarboxamide
To a solution of the corapound obtained in Example 269 (100 mg) in ethanol
(4 ml) was added 40% MeNH.sub.2 -methanol (12 ml), and the mixture was
stirred for 4 hours with heating under reflux. The solvent was evaporated
and the residue was dissolved in ethyl acetate. The solution was washed
with water, dried and evaporated to yield the title compound as colorless
crystals (65 mg).
Melting point: 173.degree.-174.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.57 (2H, s), 2.62 (1H, s),
3.13 (2H, d, J=4.8 Hz), 3.14 (1H, d, J=5 Hz), 3.52 (1/3H, d, J=15.8 Hz),
4.39 (2/3H, d, J=14.5 Hz), 4.60 (1/3H, d, J=15.8 Hz), 4.69 (2/3H, d,
J=14.5 Hz), 5.14 (2/3H, b), 5.32 (1/3H, b), 7.12-7.85 (12H, m)
EXAMPLE 272
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-2-methylthio-4-phenyl-3-quinoli
necarboxamide
To a solution of the compound obtained in Example 269 (100 mg) in THF (6
ml)-methanol (2 ml) was added 15% MeSNa in water (4 ml), and the mixture
was stirred for 8 hours with heating under reflux. The solvent was
evaporated and the residue was dissolved in ethyl acetate. The solution
was washed with water, dried and evaporated to yield the title compound as
colorless crystals (55 mg).
Melting point: 144.degree.-145.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.65 (3H, s), 2.77 (3H, s),
4.50 (1H, d, J=15 HZ), 4.70 (1H, d, J=15 Hz), 7.29-8.05 (12H, m)
EXAMPLE 273
N-›3,5-Bis(trifluoromethyl)benzyl!-1-chloro-4-(4-fluorophenyl)-N-methyl-3-i
soquinolinecarboxamide
The compound obtained in Example 178 (200 mg) was reacted with phosphorus
oxychloride (3 ml) by a method similar to Example 269 to yield the title
compound as colorless crystals (165 mg).
Melting point: 142.degree.-143.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.79 (2H, s), 2.86
(1H, s), 4.43 (2/3H, s), 4.69 (4/3H, s), 7.06-7.81 (10H, m), 8.44-8.49
(1H, m)
EXAMPLE 274
N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-N-methyl-3-isoquinoli
necarboxamide
The compound obtained in Example 273 was reacted by a method similar to
Example 224 (catalytic reduction) to yield the title compound as colorless
crystals.
Melting point: 134.degree.-135.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.76
(3.times.5/7H, s), 2.85 (3.times.2/7H, s), 4.39 (2.times.2/7, s), 4.71
(2.times.5/7H, s), 7.07-7.81 (10H, m), 8.07-8.12 (1H, m), 9.28 (2/7H, s),
9.32 (5/7H, s)
EXAMPLE 275
N-›3,5-Bis(trifluoromethyl)benzyl!-1-chloro-N-methyl-4-phenyl-3-isoquinolin
ecarboxamide
The compound obtained in Example 172 was reacted with phosphorus
oxychloride by a method similar to Example 269 to yield the title compound
as colorless crystals.
Melting point: 176.degree.-177.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.75 (3.times.3/4H, s),
2.82 (3/4H, s), 4.42 (1/2H, s), 4.67 (3/2H, s), 7.30-7.83 (11H, m), 8.46
(1H, m)
EXAMPLE 276
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-4-phenyl-3-isoquinolinecarboxam
ide
The compound obtained in Example 275 was reacted by a method similar to
Example 224 (catalytic reduction) to yield the title compound as colorless
crystals.
Melting point: 139.degree.-140.degree. C. (recrystallized from hexane) NMR
(200 MHz, CDCl.sub.3) ppm: 2.73 (3.times.3/4H, s), 2.82 (3/4H, s) 4.36
(1/2H, s), 4.70 (3/2H, s), 7.33-7.82 (11H, m), 8.10 (1H, m), 9.32 (1H, m)
EXAMPLE 277
N-›3,5-Bis(trifluoromethyl)benzyl!-1-methoxy-N-methyl-4-phenyl-3-isoquinoli
necarboxamide
The compound obtained in Example 275 was reacted with sodium methoxide by a
method similar to Example 270 to yield the title compound as colorless
crystals.
Melting point: 129.degree.-130.degree. C. (recrystallized from isopropyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.75, 2.77 (total 3H, each
s), 4.07 (2/5.times.3H, s), 4.19 (3/5.times.3H, s), 4.36 (2/5.times.2H,
s), 4.68(3/5.times.2H, s), 7.28-7.70 (9H, m), 7.78 (2H, m), 8.31 (1H, m)
EXAMPLE 278
N-›3,5-Bis(trifluoromethyl)benzyl!-N-methyl-1-methylamino-4-phenyl-3-isoqui
nolinecarboxamide
The compound obtained in Example 275 was reacted with methylamine by a
method similar to Example 271 to yield the title compound as colorless
crystals.
Melting point: 213.degree.-214.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.74, 2.77 (total
3H, each s), 3.11 (3/7.times.3H, d, J=5.0 Hz), 3.22 (4/7.times.3H, d,
J=4.8 Hz), 4.39 (3/7.times.2H, s), 4.68 (4/7.times.2H, s), 5.44 (1H, m),
7.33-7.67 (10H, m), 7.79 (2H, bs)
EXAMPLE 279
3,4-cis-N-›3,5-Bis(trifluoromethyl)benzyl!-1,2,3,4-tetrahydro-N,2-dimethyl-
1-oxo-4-phenyl-3-isoquinolinecarboxamide
3,4-cis-1,2,3,4-Tetrahydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxlic
acid ›prepared from 2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic
acid methyl ester, by converting to the reduced compound (3,4-cis) by
stirring for 6 hours at 90.degree. C. in the presence of 10%
palladium-carbon in acetic acid in a hydrogen atmosphere, followed by
hydrolysis in hydrochloric acid-acetic acid at 110.degree. C.! was reacted
with N-›3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar to
Example 101 to yield the title compound.
Melting point: 226.degree.-227.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
EXAMPLE 280
3,4-trans-N-›3,5-Bis(trifluoromethyl)benzyl!-4-(4-fluorophenyl)-1,2,3,4-tet
rahydro-N,2-dimethyl-1-oxo-3-isoquinolinecarboxamide
The compound obtained in Reference Example 2 was reacted with
N-›3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar to
Example 101 to yield the title compound.
Melting point: 171.degree.-172.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 281
3,4-cis-N-›3,5-Bis(trifluoromethyl)benzyl!-3,4-dihydro-N-methyl-1-oxo-4-phe
nyl-1H-2-benzopyran-3-carboxamide
3,4-cis-3,4-Dihydro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid
›prepared from 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid by
stirring for 4 hours at 90.degree. C. in the presence of 10%
palladium-carbon in acetic acid in a hydrogen atmosphere! was reacted with
N-›3,5-bis(trifluoromethyl)benzyl!methylamine by a method similar to
Example 101 to yield the title compound.
Melting point: 160.degree.-161.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
EXAMPLE 282
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N-methyl-1-oxo-4-phenyl-2-›2
-(N,N,N-trimethylammonium)ethyl!-3-isoquinolinecarboxamide
A solution of the compound obtained in Example 184 (free form) (65 mg) in
methanol (2 ml) was added methyl iodide (0.5 ml), and the mixture was
stirred at room temperature for 1.5 hours. Evaporation of the solvent
yielded the title compound as colorless crystals (72 mg).
Melting point: 242.degree.-243.degree. C. (recrystallized from
methanol-dichloromethane-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.02
(3H, s), 3.65 (9H, s), 3.70-4.05 (2H, b), 4.34 (1H, d, J=14.2 Hz),
4.52-4.80 (1H, b), 4.90-5.15 (1H, b), 5.42 (1H, d, J=14.2 Hz), 7.05-7.30
(6H, m), 7.42 (2H, s), 7.58 (2H, m), 7.76 (1H, s), 8.44 (1H, m)
EXAMPLE 283
N-›3,5-Bis(trifluoromethyl)phenyl!-6-chloro-1,2-dihydro-N-methyl-1-oxo-4-ph
enyl-3-isoquinolineacetamide
The compound obtained Example 223 was reacted by a method similar to
Example 102(C) to yield the title compound.
Melting point: 181.degree.-182.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.51 (2H, b), 3.30
(3H, s), 3.67 (3H, s), 6.92 (1H, bd, J=1.8 Hz), 7.10-7.65 (8H, m), 7.76
(1H, bs), 8.44 (1H, d, J=8.6 Hz)
EXAMPLE 284
3,5-Bis(trifluoromethyl)benzyl
1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxylate
A mixture of 2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid (140
mg), acetone (5 ml), DMF (1 ml), potassium carbonate (70 mg) and
3,5-bis(trifluoromethyl)benzyl bromide (0.11 ml) was stirred with heating
under reflux for 1 hour, and then concentrated. To the concentrate was
added water, and the mixture was extracted withd ethyl acetate. The
extract was washed with water, dried, and evaporated to yield the title
compound as colorless crystals (185 mg).
Melting point: 153.degree.-154.degree. C. (recrystallized from
methanol-ethyl ether)
EXAMPLE 285
N-›3,5-Bis(trifluoromethyl)benzyl!-1,2-dihydro-N,2-dimethyl-4-phenyl-1-thio
xo-3-isoquinolinecarboxamide
A mixture of the compound obtained in Example 157 (52 mg), dioxane (3 ml)
and phosphorous pentasulfide (44 mg) was refluxed for 4 hours. To the
mixture was added water, and extracted with ethyl acetate. The extract was
washed with aqueous sodium hydrogen carbonate and water, dried and
evaporated. The residue was purified by silica gel column chromatography
to yield the title compound as colorless crystals (35 mg).
Melting point: 145.degree.-147.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.79 (3H, s), 4.18 (3H, s),
4.24 (1H, d, J=14.6 Hz), 4.80 (1H, d, J=14.6 Hz), 7.16-7.89 (6H, m), 7.51
(2H, s), 7.60 (2H, m), 7.81 (1H, s), 9.23 (1H, m)
The compounds of Example 286 to 289 were obtained using the corresponding
2-oxo-2H-1-benzopyran-3-acetic acids and anilies by a method similar to
Example 1(A).
EXAMPLE 286
N-›2,6-Bis(2,2,2-trifluoroethoxy)phenyl!-6-chloro-4-(2-methylphenyl)-2-oxo-
2H-1-benzopyran-3-acetamide
Melting point: 214.degree.-216.degree. C. (recrystallized from isopropyl
ether--ethyl acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.07 (3H, s), 3.34
(1H, d, J=14.0 Hz), 3.54 (1H, d, J=13.6 Hz), 4.33 (4H, q, J=8.2 Hz), 6.67
(2H, d, J=8.4 Hz), 6.85 (1H, d, J=2.2 Hz), 7.17 (1H, d, J=8.4 Hz),
7.23-7.51 (6H, m), 7.60 (1H, bs)
EXAMPLE 287
6-Chloro-4-(2-methylphenyl)-2-oxo-N-(2,4,6-trifluorophenyl)-2H-1-benzopyran
-3-acetamide
Melting point: 225.degree.-227.degree. C. (recrystallized from isopropyl
ether--ethyl acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.08 (3H, s), 3.38
(1H, d, J=13.6 Hz), 3.54 (1H, d, J=14.2 Hz), 6.70 (2H, ddd, J=1.2, 8.6,
8.6 Hz), 6.87 (1H, d, J=2.4 Hz), 7.10-7.19 (1H, m), 7.33-7.53 (5H, m),
7.65 (1H, bs)
EXAMPLE 288
6-Chloro-2-oxo-4-(2-trifluoromethylphenyl)-N-(2,4,6-trifluorophenyl)-2H-1-b
enzopyran-3-acetamide
Melting point: 247.degree.-249.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 3.10 (1H, d, J=14.4 Hz), 3.73 (1H,
d, J=14.2 Hz), 6.65-6.76 (3H, m), 7.34-7.50 (3H, m), 7.59 (1H, bs),
7.62-7.80 (2H, m), 7.90 (1H, dd, J=1.6, 7.0 Hz)
EXAMPLE 289
N-›2,6-Bis(2,2,2-trifluoroethoxy)phenyl!-6-chloro-4-(2-methoxyphenyl)-2-oxo
-2H-1-benzopyran-3-acetamide
Melting point: 243.degree.-245.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 3.35 (1H, d, J=14.0 Hz), 3.63 (1H,
d, J=14.2 Hz), 3.70 (3H, s), 4.22-4.38 (4H, m), 6.69 (2H, d, J=8.4 Hz),
6.94 (1H, d, J=2.2 Hz), 7.08 (1H, d, J=8.6 Hz), 7.13-7.35 (4H, m),
7.42-7.58 (2H, m), 7.63 (1H, bs)
Reference Example 1
4-(2-Chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylic
acid
Process 1:
To a solution of
4-(2-chlorophenyl)-1,2-dihydro-6,7-dimethyl-2-oxo-3-quinolinecarboxylic
acid ethyl ester (2.0 g) in DMF (20 ml) was added sodium hydride (60% in
oil) (270 mg), followed by stirring at room temperature for 30 minutes. To
this solution was added isopropyl iodide (0.9 ml), followed by stirring at
70.degree. C. for 5 hours. After the mixture was cooled, ethyl acetate was
added, and this mixture was washed successively wfth dilute hydrochloric
acid, aqueous potassium carbonate and Water and then dried, after which
the solvent was distilled off. The residue was subjected to silica gel
column chromatography (hexane:ethyl acetate=5:1), to yield
4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylic
acid ethyl ester as colorless crystals (1.72 g).
Melting point: 96.degree.-97.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.01 (3H, t, J=7.1 Hz), 1.42
(6H, d, J=6.2 Hz), 2.26 (3H, s), 2.41 (3H, s), 4.00-4.16 (2H, m), 5.57
(1H, m), 6.92 (1H, s), 7.20-7.55 (4H, m), 7.64 (1H, s)
Elemental analysis (for C.sub.23 H.sub.24 NO.sub.3 Cl):
Calculated (%): C, 69.43; H, 6.08; N, 3.52
Found (%): C, 69.19; H, 5.99; N, 3.40
Process 2:
To the compound obtained in Process 1 (1.64 g) were added ethanol (28 ml),
water (7 ml) and potassium hydroxide (1.09 g), followed by heating under
reflux for 1 hour. After the solvent was distilled off, the residue was
acidified with dilute hydrochloric acid and then-extracted with ethyl
acetate. The extract was washed with saturated aqueous sodium chloride and
dried, after which the solvent was distilled off, to yield the title
compound as colorless crystals (1.31 g).
Melting point: 184.degree.-186.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.49 (6H, d, J=6.2 Hz),
2.26 (3H, s), 2.43 (3H, s), 5.73 (1H, m), 6.92 (1H, s), 7.10-7.60 (4H, m),
7.66 (1H, s)
Elemental analysis (for C.sub.21 H.sub.20 NO.sub.3 Cl):
Calculated (%): C, 68.20; H, 5.45; N, 3.79
Found (%): C, 68.23; H, 5.47; N, 3.78
Reference Example 2
3,4-trans-4-(4-Fluorophenyl)-1,2,3,4-tetrahydro-2-methyl-1-oxo-3-isoquinoli
necarboxylic acid
Process 1:
A mixture of 2-(4-fluorobenzoyl)benzoic acid (3.00 g),
1-hydroxybenzotriazole (2.07 g), 1,3-dicyclohexylcarbodiimide (3.00 g) and
anhydrous THF (50 ml) was stirred at room temperature for 1 hour. To this
mixture were added N-methylglycine ethyl ester hydrochloride (2.84 g) and
triethylamine (2.58 ml), followed by stirring at room temperature for 16
hours and with heating and refluxing for 4 hours. After the solvent was
distilled off, ethyl acetate was added to the residue, and the insoluble
crystals were separated by filtration. The flitrate was washed
successively with water, aqueous sodium hydrogen carbonate, water, dilute
hydrochloric acid and water and then dried, after which the solvent was
distilled off, to yield N-›2-(4-fluorobenzoyl)benzoyl!-N-methylglycine
ethyl ester as a colorless oily substance (4.2 g).
›NMR (200 MHz, CDCl.sub.3) ppm: 1.27, 1.30 (total 3H, each t, J=7.0 Hz),
3.01, 3.06 (total 3H, each s), 4.01, 4.17 (total 2H, each s), 4.15-4.20
(2H, m), 7.0-7.9 (8H, m)!
To a solution of this oily substance in toluene (100 ml) was added
1,8-diazabicyclo›5.4.0!undec-7-en(3.0 ml), followed by heating under
reflux for 2 hours. After the solvent was distilled off, ethyl acetate was
added to the residue. This mixture was washed successively with water, 10%
aqueous potassium hydrogen sulfate and water and then dried, after which
the solvent was distilled off, to yield
4-(4-fluorophenyl)-3,4-dihydro-4-hydroxy-2-methyl-1(2H)-isoquinoline-3-car
boxylic acid ethyl ester as colorless crystals. To a suspension of the
crystals in toluene (100 ml) was added p-toluenesulfonic acid hydrate (3.0
g), followed by heating under reflux for 14 hours with a water separator.
The solvent was distilled off, and ethyl acetate was added to the residue.
This mixture was washed successively with water, aqueous sodium hydrogen
carbonate and water and then dried, after which the solvent was distilled
off, to yield 4-(4-fluorophenyl)-2-methyl-1(2H)-isoquinoline-3-carboxylic
acid ethyl ester as colorless crystals (3.12 g).
Melting point: 172.degree.-173.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.00 (3H, t, J=7.0 Hz),
3.62 (3H, s), 4.07 (2H, q, J=7.0 Hz), 7.11-7.35 (5H, m), 7.53-7.60 (2H,
m), 8.50-8.55 (1H, m)
Elemental analysis (for C.sub.19 H.sub.16 NO.sub.3 F):
Calculated (%): C, 70.15; H, 4.96; N, 4.31
Found (%): C, 70.01; H, 4.86; N, 4.20
Process 2:
A mixture of the compound obtained in Process 1 (2.70 g), acetic acid (50
ml) and 5% palladium-carbon (2.00 g) was stirred at 70.degree. C. in a
hydrogen atmosphere for 1 hour. After the mixture was cooled and then
filtered, the filtrate was distilled to remove the solvent. The residue
was dissolved in ethyl acetate and washed successively with water, aqueous
potassium carbonate and water and then dried, after which the solvent was
distilled off, to yield
3,4-cis-4-(4-fluorophenyl)-1,2,3,4-tetrahydro-2-methyl-1-oxo-3-isoquinolin
ecarboxylic acid ethyl ester as colorless crystals (2.43 g).
Melting point: 151.degree.-153.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.98 (3H, t, J=7.2
Hz), 3.12 (3H, s), 3.78-4.03 (2H, m), 4.25 (1H, d, J=7.0 Hz), 4.92 (1H, d,
J=7.0 Hz), 6.90-7.41 (7H, m), 8.20-8.26 (1H, m)
Elemental analysis (for C.sub.19 H.sub.18 NO.sub.3 F):
Calculated (%): C, 69.71; H, 5.54; N, 4.28
Found (%): C, 69.44; H, 5.19; N, 4.31
Process 3:
To a suspension of the compound obtained in Process 2 (2.43 g) in ethanol
(50 ml) and THF (15 ml) was added 2N-NaOH (14 ml) at 0.degree. C. After
this mixture was stirred at room temperature for 1 hour, the solvent was
distilled off. Water was added to the residue, which was then washed with
ethyl ether, after which the water layer was acidified with 2N-HCl. This
mixture was extracted with ethyl acetate, the extract being washed with
water and dried, followed by solvent removal by distillation, to yield the
title compound as colorless crystals (2.12 g).
Melting point: 248.degree.-250.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3 +DMSO-d.sub.6) ppm: 3.04
(3H, s), 4.16 (1H, s), 4.73 (1H, s), 6.90-7.17 (5H, m), 7.41-7.44 (2H, m),
8.16-8.21 (1H, m)
Elemental analysis (for C.sub.17 H.sub.14 NO.sub.3 F):
Calculated (%): C, 68.22; H, 4.71; N, 4.68
Found (%): C, 68.02; H, 4.72; N, 4.58
Reference Example 3
3,4-trans-4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-qui
nolinecarboxylic acid
Process 1:
To a suspension of lithium aluminum hydride (1.4 g) in THF (50 ml) was
added dropwise a solution of
4-(2-chlorophenyl)-1,2,-dihydro-1,6,7-trimethyl-2-oxo-3-quinolinecarboxyli
c acid ethyl ester (10.0 g) in THF (100 ml) at 0.degree. C. After this
mixture was stirred at 0.degree. C. for 30 minutes, water (4 ml) was
added, followed by stirring at room temperature for 30 minutes. The
insoluble material was filtered off, the filtrate being concentrated.
After ethyl acetate was added, the residue was washed successively with
dilute hydrochloric acid and water and then dried, followed by soIvent
removal by distillation. The residue was subjected to silica gel column
chromatography (hexane:ethyl acetate=3:1) to yield
3,4-trans-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-qu
inolinecarboxylic acid ethyl ester as colorless crystals (2.94 g).
Melting point: 147.degree.-148.degree. C. (recrystallized from ethyl
acetate-isopropyl ester) NMR (200 MHz, CDCl.sub.3) ppm: 1.10 (3H, t, J=7.0
Hz), 2.14 (3H, s), 2.29 (3H, s), 3.43 (3H, s), 3.97 (1H, d, J=7.2 Hz),
4.09 (2H, q, J=7.0 Hz), 5.07 (1H, d, J=7.2 Hz), 6.64 (1H, s), 6.80-6.90
(1H, m), 6.89 (1H, s), 7.10-7.30 (2H, m), 7.40-7.50 (1H, m)
Elemental analysis (for C.sub.21 H.sub.22 NO.sub.3 Cl):
Calculated (%): C, 67.83; H, 5.96; N, 3.77
Found (%): C, 67.98; H, 6.05; N, 3.98
Process 2:
A mixture of the compound obtained in Process 1 (1.50 g), THF (10 ml),
ethanol (20 ml), water (2 ml) and sodium hydroxide (0.75 g) was stirred at
room temperature for 3 hours, after which the soivent was distilled off to
an about half mount. After water was added, the residue was washed with
ether. The water layer was acidified with dilute hydrochloric acid and
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium chloride and then dried, after which the solvent was
distilled off, to yield the title compound as colorless crystals (1.26 g).
Melting point: 128.degree.-129.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.15 (3H, s), 2.29
(3H, s), 3.42 (3H, s), 3.93 (1H, d, J=5.2 Hz), 5.07 (1H, d, J=5.2 Hz),
6.70-6.80 (1H, m), 6.74 (1H, s), 6.89 (1H, s), 7.03-7.45 (3H, m)
Elemental analysis (for C.sub.19 H.sub.18 NO.sub.3 Cl):
Calculated (%): C, 66.38; H, 5.28; N, 4.07
Found (%): C, 66.22; H, 5.16; N, 4.03
Reference Example 4
3,4-trans-6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineca
rboxylic acid
Process 1:
6-Chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylic acid
ethyl ester was reacted in substantially the same manner as in Process 1
of Reference Example 3 to yield
3,4trans-6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineca
rboxylic acid ethyl ester as colorless crystals.
Melting point: 83.degree.-84.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.05 (3H, t, J=7.1 Hz), 3.41
(3H, s), 3.89 (1H, d, J=9.4 Hz), 4.00-4.15 (2H, m), 4.58 (1H, d, J=9.4
Hz), 6.85 (1H, d, J=1.8 Hz), 7.00 (1H, d, J=8.6 Hz), 7.10-7.40 (6H, m)
Elemental analysis (for C.sub.19 H.sub.18 NO.sub.3 Cl):
Calculated (%): C, 66.38; H, 5.28; N, 4.07
Found (%): C, 66.36; H, 5.16; N, 4.12
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 2 of Reference Example 3 to yield the title compound
as colorless crystals.
Melting point: 138.degree.-139.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.41 (3H, s), 3.93
(1H, d, J=8.0 Hz), 4.58 (1H, d, J=8.0 Hz), 5.20 (1H, bs), 6.80-7.40 (8H,
m)
Elemental analysis (for C.sub.17 H.sub.14 NO.sub.3 Cl):
Calculated (%): C, 64.67; H, 4.47; N, 4.44
Found (%): C, 64.35; H, 4.52; N, 4.57
Reference Example 5
3,4-trans-4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-3-quinoline
carboxylic acid
Process 1:
To a mixture of 4-(2-chlorophenyl)-6,7-dimethyl-3-quinolinecarboxylic acid
ethyl ester (26.5 g), sodium borohydride (6.0 g) and ethanol (150 ml) was
heated under reflux for 2 hours. After the solvent was distilled off,
water was added to the residue, followed by extraction with ethyl acetate.
After the extract was washed with water and dried, the solvent was
distilled off. The residue was subjected to silica gel column
chromatography (ethyl acetate:hexane=3:1) to yield
4-(2-chlorophenyl)-1,4-dihydro-6,7-dimethyl-3-quinolinecarboxylic acid
ethyl ester as colorless crystals (5.0 g).
Melting point: 204.degree.-209.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.13 (3H, t, J=7.2
Hz), 2.07 (3H, s), 2.12 (3H, s), 3.95-4.15 (2H, m), 5.74 (1H, s), 6.34
(1H, d, J=5.4 Hz), 6.46 (1H, s), 6.94 (1H, s), 6.95-7.20 (2H, m),
7.25-7.35 (2H, m), 7.61 (1H, d, J=6.2 Hz)
Elemental analysis (for C.sub.20 H.sub.20 NO.sub.2 Cl):
Calculated (%): C, 70.27; H, 5.90; N, 4.10
Found (%): C, 70.02; H, 5.84; N, 4.07
Process 2:
To a solution of the compound obtained in Process 1 (2.65 g) in DMF (40 ml)
was added 60% sodium hydride (60% in oil) (0.35 g), followed by stirring
at room temperature for 15 minutes. After this mixture was cooled to
0.degree. C., 3 ml of methyl iodide was added, followed by stirring at
0.degree. C. for 30 minutes. After dilute hydrochloric acid was added, the
mixture was extracted with ethyl acetate. The extract was washed with
water and then dried, after which the solvent was distilled off, to yield
4-(2-chlorophenyl)-1,4-dihydro-1,6,7-trimethyl-3-quinolinecarboxylic acid
ethyl ester as colorless crystals (2.32 g).
Melting point: 200-201.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.12 (3H, t, J=7.2
Hz), 2.09 (3H, s), 2.19 (3H, s), 3.35 (3H, s), 3.95-4.10 (2H, m), 5.74
(1H, s), 6.62 (1H, s), 6.97 (1H, s), 6.98-7.15 (2H, m), 7.20-7.35 (2H, m),
7.52 (1H, s)
Elemental analysis (for C.sub.21 H.sub.22 NO.sub.2 Cl.multidot.0.1H.sub.2
O):
Calculated (%): C, 70.52; H, 6.26; N, 3.92
Found (%): C, 70.39; H, 6.32; N, 3.82
Process 3:
While stirring at room temperature a mixture of the compound obtained in
Process 2 (2.2 g), methanol (30 ml), methanol containing 20% hydrogen
chloride (10 ml) and THF (10 ml), a solution of sodium cyanoborohydride
(1.0 g) in methanol (15 ml) was gradually added dropwise. After stirring
at room temperature for 1 hour, the mixture was alkalinized with aqueous
potassium carbonate and then extracted with ethyl acetate. The extract was
washed with saturated aqueous sodium chloride and dried, after which the
solvent was distilled off, to yield
4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-3-quinolinecarboxyli
c acid ethyl ester as a pale yellow oily substance (2.44 g).
NMR (200 MHz, CDCl.sub.3) ppm: 1.13 (3H, t, J=7.1 Hz), 2.04 (3H, s), 2.21
(3H, s), 2.93 (2.5H, s), 3.00-3.50 (3H, m), 3.01 (0.5H, s), 4.00-4.18 (2H,
m), 4.95 (0.87H, d, J=5.8 Hz), 5.09 (0.13H, d, J=5.4 Hz), 6.45-6.66 (2H,
m), 6.85-7.45 (4H, m)
Process 4:
To the compound obtained in Process 3 (2.37 g) were added ethanol (40 ml),
water (10 ml) and potassium hydroxide (2.0 g), followed by stirring at
room temperature overnight. After the solvent was distilled off, the
residue was weakly acidified (pH 3 to 4) with dilute hydrochloric acid and
then extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium chloride and dried, after which the solvent was distilled
off, to yield the title compound as colorless crystals (1.51 g).
Melting point: 196.degree.-199.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.08 (3H, s), 2.23
(3H, s), 3.09 (3H, s), 3.25-3.60 (3H, m), 4.92 (1H, d, J=5.6 Hz),
5.50-6.80 (1H, brs), 6.59 (1H, s), 6.90 (1H, s), 6.95 (1H, m), 7.10-7.45
(3H, m)
Elemental analysis (for C.sub.19 H.sub.20 NO.sub.2 Cl.multidot.1.0.7H.sub.2
O):
Calculated (%): C, 66.64; H, 6.30; N, 4.09
Found (%): C, 66.53; H, 6.00; N, 3.85
Reference Example 6
1,2,3,4-Tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetic acid
Process 1:
A mixture of 1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylic acid
ethyl ester (30.7 g), 10% palladium-carbon (2.0 g) and acetic acid (150
ml) was stirred at 80.degree. C. for 24 hours in a hydrogen atmosphere (5
atm). After the catalyst was filtered off, the filtrate was concentrated.
After ethyl acetate was added, the residue was washed successively with
potassium carbonate and water and then dried, after which the solvent was
distilled off, to yield
3,4-trans-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylic
acid ethyl ester as colorless crystals (27.9 g).
Melting point: 80.degree.-81.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.04 (3H, t, J=7.1
Hz), 3.43 (3H, s), 3.91 (1H, d, J=9.6 Hz), 4.00-4.15 (2H, m), 4.16 (1H, d,
J=9.6 Hz), 6.80-7.40 (9H, m)
Elemental analysis (for C.sub.19 H.sub.19 NO.sub.3):
Calculated (%): C, 73.77; H, 6.19; N, 4.53
Found (%): C, 73.53; H, 6.12; N, 4.52
Process 2:
A mixture of the compound obtained in Process 1 (20 g), sodium hydride (60%
in oil) (2.72 g) and DMF (200 ml) was stirred at room temperature for 30
minutes. After methyl bromoacetate (6.73 ml) was added, the mixture was
stirred at room temperature overnight. After dilute hydrochloric acid was
added, the mixture was extracted with ethyl acetate. The extract was
washed with aqueous potassium carbonate and water and then dried, followed
by solvent removal by distillation. The residue was subjected to silica
gel column chromatography (hexane:ethyl acetate=3:1) to yield
3-ethoxycarbonyl-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolinecar
boxylic acid methyl ester as a pale yellow oily substance. To this oily
substance were added ethanol (160 ml), water (40 ml) and potassium
hydroxide (10 g), followed by overnight heating and refluxing. After the
solvent was distilled off, dilute hydrochloric acid was added, and the
mixture was extracted with ethyl acetate. The extract was washed with
saturated aqueous sodium chloride and then dried, after which the solvent
was distilled off. After pyridine (100 ml) was added, the residue was
heated under reflux for 30 minutes. After the solvent was distilled off,
the residue was acidified with dilute hydrochloric acid and then extracted
with ethyl acetate. The extract was washed with saturated aqueous sodium
chloride and then dried, after which the solvent was distilled off, to
yield the title compound (trans:cis=about 3:2 mixture) as a white foamy
substance (19.1 g).
NMR (200 MHz, CDCl.sub.3) ppm: 2.27-2.65 (1.6H, ml, 2.75-3.00 (0.4H, m),
3.25-3.60 (1H, m), 3.44 (1.8H, s), 3.48 (1.2H, s), 4.16 (0.6H, d, J=13.0
Hz), 4.19 (0.4H, d, J=6.8 Hz), 6.60-6.70 (0.6H, m), 6.90-7.45 (8.4H, m)
Reference Example 7
4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinolineacetic acid
Process 1:
4-(2-Chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-3-quinolineacetic acid ethyl
ester was reacted in substantially the same manner as in Process 1 of
Reference Example 3 to yield
3,4-trans-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinoline
carboxylic acid ethyl ester as colorless crystals.
Melting point: 131.degree.-133.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.08 (3H, t, J=7.2
Hz), 3.45 (3H, s), 4.00-4.20 (2H, m), 4.03 (1H, d, J=8.0 Hz), 5.14 (1H, d,
J=8.0 Hz), 6.80-7.50 (8H, m)
Elemental analysis (for C.sub.19 H.sub.18 NO.sub.3 Cl):
Calculated (%): C, 66.38; H, 5.28; N, 4.07
Found (%): C, 66.03; H, 5.17; N, 4.06
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 2 of Reference Example 6 to yield the title compound
(trans:cis=about 6:1 mixture) as colorless crystals.
Melting point: 177.degree.-180.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.34 (0.86, dd,
J=16.0, 3.8 Hz), 2.45-2.80 (0.28, m), 2.67 (0.86H, dd, J=16.0, 8.8 Hz),
3.35-3.70 (1H, m), 3.45 (2.58H, s), 3.49 (0.42H, s), 4.77 (0.86H, d, J=13
Hz), 5.00 (0.14H, d, J=7.0 Hz), 6.58 (0.86H, d, 5=7.4 Hz), 6.90-7.55
(7.14H, m)
Elemental analysis (for C.sub.18 H.sub.16 NO.sub.3 Cl.multidot.0.2H.sub.2
O):
Calculated (%): C, 64.85; H, 4.96; N, 4.20
Found (%): C, 64.80; H, 4.74; N, 4.23
Reference Example 8
1,2,3,4-Tetrahydro-6,7-dimethoxy-1-methyl-2-oxo-4-phenyl-3-quinolineacetic
acid
Process 1:
1,2-Dihydro-6,7-dimethoxy-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylic
acid ethyl ester was reacted in substantially the same manner as in
Process 1 of Reference Example 7 to yield
3,4-trans-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methyl-2-oxo-4-phenyl-3-quino
linecarboxylic acid ethyl ester as colorless crystals.
Melting point: 157.degree.-159.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.07 (3H, t, J=7.1
Hz), 3.43 (3H, s), 3.71 (3H, s), 3.86 (1H, d, J=8.0 Hz), 3.93 (3H, s),
4.00-4.20 (2H, m), 4.55 (lH, d, J=8.0 Hz), 6.44 (1H, s), 6.65 (1H, s),
7.10-7.40 (5H, m)
Elemental analysis (for C.sub.21 H.sub.23 NO.sub.5):
Calculated (%): C, 68.28; H, 6.28; N, 3.79
Found (%): C, 68.11; H, 6.36; N, 3.77
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 2 of Reference Example 7 to yield the title compound
a white foamy substance.
NMR (200 MHz, CDCl.sub.3) ppm: 2.32 (0.33H, dd, J=17.0, 6.2 Hz), 2.39
(0.67H, dd, J=16.0, 5.0 Hz), 2.57 (0.67H, dd, J=16.0, 7.4 Hz), 2.83
(0.33H, dd, J=17.0, 7.6 Hz), 3.20-3.60 (1H, m), 3.42 (2H, s), 3.48 (1H,
s), 3.62 (2H, s), 3.81 (1H, s), 3.92 (3H, s), 4.09 (0.67H, d, J=11.0 Hz),
4.09 (0.33H, d, J=6.2 Hz), 6.22 (0.67H, s), 6.60-6.67 (1.33H, m),
6.90-7.40 (5H, m)
Reference Example 9
6-Chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenyl-3-quinolineacetic
acid
Process 1:
To a solution of
6-chloro-1,2,3,4-tetrahydro-4-methyl-2-oxo-4-phenylquinoline (6.0 g) in
DMF (50 ml) was added sodium hydride (60% in oil) (0.98 g), followed by
stirring at room temperature for 30 minutes. After this mixture was cooled
to 0.degree. C., methyl iodide (3 ml) was added, followed by stirring at
room temperature for further 30 minutes. After dilute hydrochloric acid
was added, the mixture was extracted with ethyl acetate. The extract was
washed with water and then dried, after which the solvent was distilled
off, to yield
6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenylquinoline as
colorless crystals (5.58 g).
Melting point: 125.degree.-126.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.66 (3H, s), 2.70
(1H, d, J=16.0 Hz), 3.20 (1H, d, J=16.0 Hz), 3.24 (3H, s), 6.95 (1H, d,
J=8.4 Hz), 7.10-7.35 (7H, m)
Elemental analysis (for C.sub.17 H.sub.16 NOCl):
Calculated (%): C, 71.45; H, 5.64; N, 4.90
Found (%): C, 71.46; H, 5.66; N, 4.88
Process 2:
While stirring at -78.degree. C. in an argon atmosphere a solution of the
compound obtained in Process 1 (5.0 g) in THF (60 ml), a solution of 2M
lithium sodium isopropylamide in THF-heptane (14.6 ml) was added dropwise.
After the mixture was stirred for 30 minutes, a solution of methyl
bromoacetate (2.9 ml) in THF (15 ml) was added dropwise, followed by
stirring at -78.degree. C. for 30 more minutes. After saturated aqueous
ammonium chloride was added, the mixture was extracted with ethyl acetate.
The extract was washed successively with dilute hydrochloric acid and
water and then dried, followed by solvent removal by distillation. The
residue was subjected to silica gel column chromatography (hexane:ethyl
acetate=2:1) to yield
6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenyl-3-quinolineacetic
acid methyl ester as a colorless oily substance. To this oily substance
were added methanol (64 ml), water (26 ml) and sodium hydroxide (8 g),
followed by stirring overnight at room temperature. After the solvent was
distilled off, water was added, and the mixture was washed with ether. The
aqueous layer was acidified with dilute hydrochloric acid and then
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium chloride and then dried, after which the solvent was
distilled oil, to yield the title compound as colorless crystals (5.27 g)
.
Melting point: 166.degree.-168.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 1.42 (3H, s), 1.88 (1H, dd,
J=16.0, 2.6 Hz), 2.69 (1H, dd, J=16.0, 10.0 Hz), 3.42 (3H, s), 3.68 (1H,
dd, J=10.0, 2.6 Hz), 6.52 (1H, d, J=2.4 Hz), 6.96 (1H, d, J=8.6 Hz),
7.15-7.50 (6H, m)
Elemental analysis (for C.sub.19 H.sub.18 NO.sub.3 Cl):
Calculated (%): C, 66.38; H, 5.28; N, 4.07
Found (%): C, 66.40; H, 5.12; N, 4.30
Reference Example 10
4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-1,6,7-trimethyl-2-oxo-3-quinolineacet
ic acid
The compound obtained in Process 1 of Reference Example 3 was reacted in
substantially the same manner as in Process 2 of Reference Example 6 to
yield the title compound (trans:cis=about 5:1 mixture) as colorless
crystals.
Melting point: 210.degree.-215.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.09 (2.5H, s),
2.16 (0.5H, s), 2.27 (3H, s), 2.33 (0.83H, dd, J=16.0, 4.2 Hz), 2.35-2.80
(0.34H, m), 2.66 (0.83H, dd, J=16.0, 8.0 Hz), 3.30-3.70 (1H, m), 3.43
(2.5H, s), 3.47 (0.5H, s), 4.68 (0.83H, d, J=12.0 Hz), 4.91 (0.17H, d,
J=7.0 Hz), 6.33 (0.83H, s), 6.80-7.50 (5.17H, m)
Elemental analysis (for C.sub.20 H.sub.20 NO.sub.3 Cl):
Calculated (%): C, 67.13; H, 5.63; N, 3.91
Found (%): C, 66.88; H, 5.71; N, 3.81
Reference Example 11
6-Chloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-quinolineac
etic acid
Process 1:
6-Chloro-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxyli
c acid ethyl ester was reacted in substantially the same manner as in
Process 1 of Reference Example 3 to yield
3,4-trans-6-chloro-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-1-methyl-2-oxo-3-
quinolinecarboxylic acid ethyl ester as colorless crystals.
Melting point: 103.degree.-104.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.10 (3H, t, J=7.1
Hz), 3.43 (3H, s), 4.00-4.20 (2H, m), 4.01 (1H, d, 5=8.2 Hz), 5.11 (1H, d,
J=8.2 Hz), 6.80-7.50 (7H, m)
Elemental analysis (for C.sub.19 H.sub.17 NO.sub.3 Cl.sub.2):
Calculated (%): C, 60.33; H, 4.53; N, 3.70
Found (%): C, 60.28; H, 4.35; N, 3.78
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 2 of Reference Example 6 to yield the title compound
(trans:cis=about 4:1 mixture) as a white foamy substance.
NMR (200 MHz, CDCl.sub.3) ppm: 2.34 (0.8H, dd, J=16.0, 4.2 Hz), 2.36-2.80
(0.4H, m), 2.63 (0.8H, dd, J=16.0, 8.0 Hz), 3.35-3.70 (1H, m), 3.42 (2.4H,
s), 3.46 (0.6H, s), 4.78 (0.8H, d, J=13 Hz), 4.98 (0.2H, d, J=6.8 Hz),
6.54 (0.8H, s), 6.75-7.60 (6.2H, m)
Reference Example 12
6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetic acid
The compound obtained in Process 1 of Reference Example 4 was reacted in
substantially the same manner as in Process 2 of Reference Example 6 to
yield the title compound (trans:cis=about 4:1 mixture) as a white foamy
substance.
NMR (200 MHz, CDCl.sub.3) ppm: 2.25-2.60 (1.8H, m), 2.80-2.95 (0.2H, m),
3.20-3.60 (1H, m), 3.41 (2.4H, s), 3.45 (0.6H, s), 4.14 (0.2H, d, J=7.0
Hz), 4.16 (0.8H, d, J=12 Hz), 6.63 (0.8H, s), 6.90-7.50 (7.2H, m)
Elemental analysis (for C.sub.18 H.sub.16 NO.sub.3 Cl):
Calculated (%): C, 65.56; H, 4.89; N, 4.25
Found (%): C, 65.75; H, 4.98; N, 4.18
Reference Example 13
3,4-cis-6-Chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid
Process 1:
To a solution of 6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid
ethyl ester (4.4 g) in ethanol (300 ml) was added platinum oxide (0.30 g),
followed by stirring at room temperature in a hyarogen atmosphere (3 to 4
atm) for 3 hours. After the catalyst was filtered off, the flitrate was
distilled to remove the solvent, followed by treatment of the residue with
isopropyl ether, to yield
6-chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid
ethyl ester as colorless crystals (2.24 g).
Melting point: 93.degree.-95.degree. C. (recrystallized from isopropyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.09 (3H, t, J=7.0 Hz), 3.95 (1H, d,
J=8.2 Hz), 4.11 (2H, q, J=7.0 Hz), 6.94 (1H, d, J=2.4 Hz), 7.0-7.3 (7H, m)
Elemental analysis (for C.sub.18 H.sub.15 O.sub.4 Cl):
Calculated (%): C, 65.36; H, 4.57
Found (%): C, 65.75; H, 4.61
Process 2:
To a solution of the compound obtained in Process 1 (2.20 g) in DMF (20 ml)
was added sodium hydride (60% in oil) (0.35 g) at room temperature,
followed by stirring for 0.5 hours. After methyl bromoacetate (1.4 ml) was
added, this mixture was stirred at room temperature for 2 hours, after
which dilute hydrochloric acid was added, followed by extraction with
ethyl acetate. The extract was washed with water and dried, after which
the solvent was distilled off, followed by treatment of the residue with
isopropyl ether, to yield
6-chloro-3-ethoxycarbonyl-3,4-dihydro-3-methoxycarbonylmethyl-2-oxo-4-phen
yl-2H-1-benzopyran as colorless crystals.
Melting point: 134.degree.-136.degree. C. (recrystallized from isopropyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.99 (3H, t, J=7.0 Hz), 2.69 (1H, d,
J=17.8 Hz), 3.27 (1H, d, J=17.8 Hz), 4.00 (2H, m), 5.12 (1H, s), 6.82 (1H,
bs), 7.0-7.1 (3H, m), 7.2-7.3 (1H, m), 7.4-7.5 (3H, m)
Elemental analysis (for C.sub.21 H.sub.19 O.sub.6 Cl):
Calculated (%): C, 62.61; H, 4.75
Found (%): C, 62.31; H, 4.70
Process 3:
A mixture of the compound obtained in Process 2 (1.5 g), acetic acid (10
ml) and hydrochloric acid (5 ml) was heated for 3 hours under reflux,
followed by solvent removal by distillation, to yield a mixture of the
title compound and its stereo isomer as an oily substance. This oily
substance was treated with ethyl acetate-isopropyl ether to yield the
title compound as colorless crystals (0.7 g).
Melting point: 117.degree.-119.degree. C. (recrystallized from isopropyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.37 (1H, dd, J=18.0 Hz, J=7.2 Hz),
2.86 (1H, dd, J.=17.6 Hz, J=6.4 Hz), 3.62 (1H, m), 4.31 (1H, d, J=6.6 Hz),
7.0-7.4 (8H, m)
Elemental analysis (for C.sub.17 H.sub.13 O.sub.4 Cl):
Calculated (%): C, 64.47; H, 4.14
Found (%): C, 64.35; H, 3.95
Reference Example 14
3,4-Dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid
Process 1:
To a solution of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid
ethyl ester (15.0 g) in acetic acid (150 ml) was added 10%
palladium-carbon (3.0 g), followed by stirring at 80.degree. C. in a
hydrogen atmosphere (4 to 5 atm) for 4.5 hours. After the catalyst was
filtered off, the filtrate was distilled to remove the solvent, followed
by treatment of the residue with isopropyl ether, to yield
3,4-dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid
ethyl ester as colorless crystals (12.5 g).
Melting point: 206.degree.-208.degree. C. (recrystallized from isopropyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.07 (3H, t, J=7.0 Hz), 2.25 (3H,
s), 3.94 (1H, d, J=7.6 Hz), 4.10 (2H, qd, J=7.0 Hz, J=2.0 Hz), 4.68 (1H,
d, J=7.6 Hz), 6.75 (1H, bs), 7.0-7.4 (7H, m)
Elemental analysis (for C.sub.19 H.sub.18 O.sub.4 .multidot.1/4H.sub.2 O):
Calculated (%): C, 72.48; H, 5.92
Found (%): C, 72.24; H, 5.97
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 2 of Reference Example 13 to yield
3-ethoxycarbonyl-3,4-dihydro-3-methoxycarbonylmethyl-6-methyl-2-oxo-4-phen
yl-2H-1-benzopyran as colorless crystals.
Melting point: 123.degree.-125.degree. C. (recrystallized from isopropyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.95 (3H, t, J=7 Hz), 2.21 (3H, s.),
2.71 (1H, d, J=17.8 Hz), 3.23 (1H, d, J=17.8 Hz), 3.73 (3H, s), 3.97 (2H,
m), 5.04 (1H, s), 6.63 (1H, bs), 7.0-7.2 (4H, m), 7.3-7.4 (3H, m)
Elemental analysis (for C.sub.22 H.sub.22 O.sub.6):
Calculated (%): C, 69.10; H, 5.80
Found (%): C, 68.77; H, 5.87
Process 3:
The compound obtained in Process 2 was reacted in substantially the same
manner as in Process 3 of Reference Example 13 to yield a mixture of the
trans and cis configurations of the title compound (trans:cis=about 2.5:1
mixture) as colorless crystals.
Melting point: 152.degree.-154.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.19 (3H, s), 2.55
(2H, m), 3.36 (1H, m), 4.27 (1H, d, J=12.6 Hz), 6.44 (1H, brs), 7.0-7.5
(7H, m), 2.27 (3H, s), 2.34 (1H, dd, J=17.8 Hz, J=7.6 Hz), 2.86 (1H, dd,
J=18.0 Hz, J=6.6 Hz), 3.50 (1H, m), 4.27 (1H, d, J=6.8 Hz), 7.0-7.5 (8H,
m)
Elemental analysis (for C.sub.18 H.sub.16 O.sub.4):
Calculated (%): C, 72.96; H, 5.44
Found (%): C, 72.94; H, 5.59
Reference Example 15
3,4-cis-6-Chloro-1,2,3,4-tetrahydro-1-methyl-4-phenyl-3-quinolineacetic
acid
Process 1:
6-Chloro-4-phenyl-3-quinolinecarboxylic acid ethyl ester was reacted in
substantially the same manner as in Process 1 of Reference Example 5 to
yield 6-chloro-1,4-dihydro-4-phenyl-3-quinolinecarboxylic acid ethyl ester
as colorless crystals.
Melting point: 167.degree.-168.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.18 (3H, t, J=7.1
Hz), 4.00-4.20 (2H, m), 5.08 (1H, s), 6.44 (1H, bd, J=6.2 Hz), 6.65 (1H,
d, J=9.4 Hz), 7.00-7.30 (7H, m), 7.54 (1H, d, J=6.2 Hz)
Elemental analysis (for C.sub.18 H.sub.16 NO.sub.2 Cl):
Calculated (%): C, 68.90; H, 5.14; N, 4.46
Found (%): C, 68.66; H, 5.23; N, 4.56
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 2 of Reference Example 5 to yield
6-chloro-1,4-dihydro-1-methyl-4-phenyl-3-quinolinecarboxylic acid ethyl
ester as a colorless crystals.
Melting point: 159.degree.-161.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 1MHz, CDCl.sub.3) ppm: 1.19 (3H, t,
J=7.1 Hz), 3.34 (3H, s), 4.00-4.20 (2H, m), 5.08 (1H, s), 6.80 (1H, d,
J=8.4 Hz), 7.05-7.30 (7H, m), 7.45 (1H, s)
Elemental analysis (for C.sub.19 H.sub.18 NO.sub.2 Cl):
Calculated (%): C, 69.62; H, 5.53; N, 4.27
Found (%): C, 69.60; H, 5.54; N, 4.44
Process 3:
The compound obtained in Process 2 was reacted in substantially the same
manner as in Process 3 of Reference Example 5 to yield
6-chloro-1,2,3,4-tetrahydro-1-methyl-4-phenyl-3-quinolinecarboxylic acid
ethyl ester as a mixture of stereo isomers. From this mixture, the 3,4-cis
isomer was obtained as colorless crystals.
Melting point: 138.degree.-139.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.20 (3H, t, J=7.1
Hz), 3.01 (3H, s), 3.10-3.55 (3H, m), 4.06 (2H, q, J=7.1 Hz), 4.52 (1H, d,
J=5.6 Hz), 6.62 (1H, d, J=9.0 Hz), 6.85-7.30 (7H, m)
Elemental analysis (for C.sub.19 H.sub.20 NO.sub.2 Cl):
Calculated (%): C, 69.19; H, 6.11; N,4.25
Found (%): C, 68.94; H, 5.84; N, 4.22
Process 4:
To a suspension of lithium aluminum hydride (2.0 g) in THF (50 ml) was
added dropwise a solution of the compound (cis isomer) obtained in Process
3 (4.85 g) in THF (25 ml) at room temperature, followed by stirring at
room temperature for 15 minutes. Water (2 ml) was added, followed by
stirring for 15 more minutes. After the insoluble material was filtered
off, the filtrate was concentrated. After ethyl acetate was added, the
residue was washed with water and dried, after which the solvent was
distilled off, to yield
3,4-cis-6-chloro-1,2,3,4-tetrahydro-3-hydroxymethyl-1-methyl-4-phenylquino
line as colorless crystals (3.91 g).
Melting point: 108.degree.-110.degree. C. (recrystallized from ethyl
ether-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 2.41 (1H, m), 2.99 (3H, s),
3.00-3.22 (2H, m), 3.27 (1H, dd, J=11.0, 7.2 Hz), 3.49 (1H, dd, J=11.0,
7.0 Hz), 4.20 (1H, d, J=5.2 Hz), 6.61 (1H, d, J=8.8 Hz), 6.86 (1H, d,
J=2.4 Hz), 7.00-7.35 (6H, m)
Elemental analysis (for C.sub.17 H.sub.18 NOCl):
Calculated (%): C, 70.95; H, 6.30; N, 4.87
Found (%): C, 70.52; H, 6.48; N, 5.08
Process 5:
The compound obtained in Process 4 was reacted in substantially the same
manner as in Process 2 of Reference Example 18 to yield
3,4-cis-6-chloro-3-cyanomethyl-1,2,3,4-tetrahydro-1-methyl-4-phenylquinoli
ne as colorless crystals.
Melting point: 166.degree.-168.degree. C. (recrystallized from ethyl
ether-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.03 (1H, dd,
J=17.0, 8.4 Hz), 2.14 (1H, dd, J=17.0, 7.2 Hz), 2.61 (1H, m), 3.00 (3H,
s), 3.05-3.40 (2H, m), 4.23 (1H, d, J=5.0 Hz), 6.62 (1H, d, J=8.8 Hz),
6.86 (1H, d, J=1.8 Hz), 7.00-7.40 (6H, m)
Elemental analysis (for C.sub.18 H.sub.17 N.sub.2 Cl):
Calculated (%): C, 72.84; H, 5.77; N, 9.44
Found (%): C, 72.49; H, 5.79; N, 9.23
Process 6:
The compound obtained in Process 5 was reacted in substantially the same
manner as in Process 3 of Reference Example 18 to yield the title compound
as colorless crystals.
Melting point: 192.degree.-195.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.96 (1H, dd,
J=17.0, 8.0 Hz), 2.28 (1H, dd, J=17.0, 6.6 Hz), 2.75 (1H, m), 2.98 (3H,
s), 3.05-3.20 (2H, m), 4.16 (1H, d, J=5.2 Hz), 6.61 (1H, d, J=8.8 Hz),
6.86 (1H, d, J=2.6 Hz), 6.95-7.35 (6H, m)
Elemental analysis (for C.sub.18 H.sub.18 NO.sub.2 Cl):
Calculated (%): C, 68.46; H, 5.75; N., 4.44
Found (%): C, 68.44; H, 5.96; N, 4.24
Reference Example 16
3,4-trans-1,2,3,4-Tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinea
cetic acid
Process 1:
A mixture of 2-benzoyl-4,5-dimethylbenzoic acid (11.4 g), acetone (300 ml),
DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate (12.84
g) was stirred at room temperature for 60 hours. After the solvent was
distilled off, ethyl acetate was added to the residue. This mixture was
washed with water and dried, after which the solvent was distilled off. To
the residue were added acetic acid (180 ml) and hydrochloric acid (180
ml), followed by heating at 110.degree. C. for 5 hours. After the reaction
mixture was concentrated, water was added to the concentrate, followed by
extraction with ethyl acetate. The extract was washed with water and then
dried, after which the solvent was distilled off, to yield colorless
crystals, which were recrystallized from ethyl acetate-isopropyl ether, to
yield 6,7-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid.
Melting point: 265.degree.-268.degree. C.
Process 2:
To a solution of the compound obtained in Process 1 (3.75 g) in methanol
(50 ml) was added a 40% methylamine-methanol solution (25 ml), followed by
stirring at room temperature for 2 hours. After the solvent was distilled
off, 4N-HCl-ethyl acetate (50 ml) was added to the residue, followed by
stirring at room temperature for 2 hours. After the solvent was distilled
off, water was added to the residue, the precipitated crystals were
collected by filtration and washed with water, acetone and ethyl ether, to
yield 4-phenyl-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylic acid as
colorless crystals (3.51g).
Melting point: >300.degree. C. (recrystallized from ethanol) NMR (200 MHz,
CDCl.sub.3 +DMSO-d.sub.6) ppm: 2.25 (3H, s), 2.39 (3H, s), 3.67 (3H, s),
6.91 (1H, s), 7.39-7.42 (5H, m), 8,24 (1H, s)
Elemental analysis (for C.sub.19 H.sub.17 NO.sub.3):
Calculated (%): C, 74.25; H, 5.58; N, 4.56
Found (%): C, 74.40; H, 5.50; N, 4.41
Process 3:
To a solution of the compound obtained in Process 2 (3.2 g) in DMF (30 ml)
was added sodium hydride (60% in oil) (0.50 g) while stirring the
solution, followed by addition of ethyl iodide (1.5 ml) and stirring at
room temperature for 16 hours. After the reaction mixture was
concentrated, ethyl acetate was added to the concentrate. This mixture was
washed with water, after which the solvent was distilled off, to yield
2,6,7-trimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid ethyl
ester as colorless crystals (3.3 g).
Melting point: 151.degree.-153.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 0.92 (3H, t, J=7.2
Hz), 2.26 (3H, s), 2.40 (3H, s), 3.61 (3H, s), 4.01 (2H, q, J=7.2 Hz),
6.96 (1H, s), 7.30-7.46 (1H, m), 8.27 (1H, s)
Elemental analysis (for C.sub.21 H.sub.21 NO.sub.3):
Calculated (%): C, 75.20; H, 6.31; N, 4.18
Found (%): C, 74.91; H, 6.29; N, 4.13
Process 4:
The compound obtained in Process 3 (1.0 g) was reacted in substantially the
same manner as in Process 2 of Reference Example 2 to yield
3,4-cis-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineca
rboxylic acid ethyl ester as colorless crystals (730 mg).
NMR (200 MHz, CDCl.sub.3) ppm: 0.94 (3H, t, J=7.2 Hz), 2.17 (3H, s), 2.29
(3H, s), 3.09 (3H, s), 3.72-4.02 (2H, m), 4.24 (1H, d, J=7.0 Hz), 4.84
(1H, d, J=7.0 Hz), 6.72 (1H, s), 7.24-7.38 (5H, m), 7.98 (1H, s)
Process 5:
The compound obtained in Process 4 (690 mg) was reacted in substantially
the same manner as in Process 3 of Reference Example 2 to yield
3,4-trans-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinoline
carboxylic acid as colorless crystals (610 mg).
Melting point: 248.degree.-250.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.22 (3H, s), 2.28
(3H, s), 2.99 (3H, s), 4.22 (1H, s), 4.61 (1H, s), 6.89 (1H, s), 7.05-7.25
(5H, m), 7.94 (1H, s)
Elemental analysis (for C.sub.19 H.sub.19 NO.sub.3 .multidot.1/5H.sub.2 O):
Calculated (%): C, 72.92; H, 6.25; N, 4.48
Found (%): C, 72.84; H, 6.31; N, 4.42
Process 6:
The compound obtained in Process 5 was reacted in substantially the same
manner as in Process 1 of Reference Example 18 to yield
3,4-trans-1,2,3,4-tetrahydro-3-hydroxymethyl-2,6,7-trimethyl-1-oxo-4-pheny
lisoquinoline as colorless crystals.
Melting point: 180.degree.-182.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.23 (3H, s), 2.29
(3H, s), 3.03 (3H, s), 3.63 (1H, s), 3.55-3.75 (1H, m), 3.80-3.85 (1H, m),
4.27 (1H, s), 6.92 (1H, s), 7.02-7.25 (5H, m), 7.88 (1H, s)
Elemental analysis (for C.sub.19 H.sub.21 NO.sub.2):
Calculated (%): C, 77.26; H, 7.17; N, 4.74
Found (%): C, 77.02; H, 7.27; N, 4.66
Process 7:
The compound obtained in Process 6 was reacted in substantially the same
manner as in Process 2 of Reference Example 18 to yield
3,4-trans-3-cyanomethyl-1,2,3,4-tetrahydro-2,6,7-trimethyl-1-oxo-4-phenyli
soquinoIine as colorless crystals.
Melting point: 183.degree.-184.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.27 (3H, s), 2.33
(3H, s), 2.56 (1H, dd, J=17.0, 9.2 Hz), 2.74 (1H, dd, J=17.0, 5.4 Hz),
3.01 (3H, s), 3.85-3.98 (1H, m), 4.23 (1H, s like), 6.98 (1H, s),
7.00-7.05 (2H, m), 7.20-7.30 (3H, m), 7.93 (1H, s)
Elemental analysis (for C.sub.20 H.sub.20 N.sub.2 O):
Calculated (%): C, 78.92; H, 6.62; N, 9.20
Found (%): C, 79.08; H, 6.58; N, 9.35
Process 8:
The compound obtained in Process 7 was reacted in substantially the same
manner as in Process 3 of Reference Example 18 to yield the title compound
as colorless crystals.
Melting point: 225.degree.-227.degree. C. (recrystallized from
THF-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.25 (3H, s), 2.32
(3H, s), 2.65 (1H, dd, J=16.0, 8.8 Hz), 2.76 (1H, dd, J=16.0, 5.0 Hz),
2.97 (3H, s), 4.00-4.12 (1H, m), 4.15 (1H, s like), 6.93 (1H, s),
6.95-7.10 (2H, m), 7.15-7.30 (3H, m), 7.93 (1H, s)
Elemental analysis (for C.sub.20 H.sub.21 NO.sub.3):
Calculated (%): C, 74.28; H, 6.55; N, 4.33
Found (%): C, 74.24; H, 6.49; N, 4.59
Reference Example 17
6-Chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinoxalineacetic
acid
Process 1:
6-Chloro-1,2,3,4-tetrahydro-2-oxo-4-phenylquinoxaline
›N-(4-chlorophenyl)-1,2-phenylenediamine was chloroacetylated with
chloroacetyl chloride, after which it was thermally reacted with potassium
carbonate in DMF in the presence of sodium iodide: Melting point:
210.degree.-212.degree. C. (recrystallized from ethyl acetate-isopropyl
ether): NMR (200 MHz, CDCl.sub.3) ppm: 4.26 (2H, s), 6.75-6.85 (3H, m),
7.10-7.25 (3H, m), 7.35-7.50 (2H, m), 9.26 (1H, bs)!
To a solution of this compound (4.70 g) in DMF (50 ml) was added sodium
hydride (60% in oil) (0.89 g), followed by stirring at room temperature
for 30 minutes. After the mixture was cooled to 0.degree. C., methyl
iodide (5 ml) was added, followed by stirring at room temperature
overnight. After dilute hydrochloric acid was added, the mixture was
extracted with ethyl acetate. The extract was washed with water and dried,
after which the solvent was distilled off, to yield
6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylquinoxaline as
colorless crystals (1.88 g).
Melting point: 112.degree.-114.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.42 (3H, s), 4.25
(2H, s), 6.84-7.00 (3H, m), 7.13-7.25 (3H, m), 7.35-7.50 (2H, m)
Elemental analysis (for C.sub.15 H.sub.13 N.sub.2 OCl):
Calculated (%): C, 66.06; H, 4.80; N, 10.27
Found (%): C, 66.21; H, 4.62; N, 10.44
Process 2:
While stirring a solution of the compound obtained in Process 1 (1.8 g) in
THF (40 ml) at -78.degree. C. in an argon atmosphere, a solution of 2M
lithium diisopropylamide in THF-heptane (5 ml) was added dropwise. After
the mixture was stirred for 30 minutes, a solution oft-butyl bromoacetate
(1.4 ml) in THF (5 ml) was added dropwise, followed by stirring at
-78.degree. C. for further 30 minutes. After saturated aqueous ammonium
chloride was added, the mixture was extracted with ethyl acetate. The
extract was washed successively with aqueous potassium hydrogen sulfate,
aqueous potassium carbonate and water and then dried, after which the
solvent was distilled off, to yield
6-chloro-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenyl-3-quinoxalineacetic
acid t-butyl ester as a pale yellow oily substance. To this oily substance
were added a 3N aqueous sodium hydroxide solution (10 ml) and methanol (40
ml), followed by heating under reflux for 2 hours. After the solvent was
distilled off, water was added to the residue, which was washed with
ether. The water layer was weakly acidified with dilute hydrochloric acid
and then extracted with ethyl acetate. The extract was washed with water
and dried, after which the solvent was distilled off, to yield the title
compound as colorless crystals (1.03 g).
Melting point: 152.degree.-153.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.69 (2H, d, J=6.6
Hz), 3.42 (3H, s), 4.60-5.80 (1H, bs), 4.93 (1H, t, J=6.6 Hz), 6.88 (1H, s
like), 6.97 (2H, s like), 7.10-7.40 (5H, m)
Elemental analysis (for C.sub.17 H.sub.15 N.sub.O.sub.3 Cl):
Calculated (%): C, 61.73; H, 4.57; N, 8.47
Found (%): C, 61.96; H, 4.61; N, 8.75
Reference Example 18
6-Chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolineacetic acid
Process 1:
To a solution of
6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylic acid
(4.41 g) in anhydrous THF (50 ml) were added oxalyl chloride (1.83 ml) and
DMF (one drop), followed by stirring at room temperature for 1.5 hours.
Upon solvent removal by distillation, the acid chloride was obtained as
colorless crystals (4.60 g). To a solution of this acid chloride (4.0 g)
in THF (65 ml) was added sodium borohydride (NaBH.sub.4) (1.30 g) at room
temperature, followed by stirring for 0.5 hours. Then to this solution was
added 1,2-dimethoxyethane (50 ml) and then NaBH.sub.4 (0.30 g), followed
by stirring at 50.degree. C. for 1 hour. Then, NaBH.sub.4 (0.20 g) was
added to the solution, followed by stirring at the room temperature for 1
hour. The separated precipitate was filtered off, and the flitrate was
added to a dilute hydrochloric acid solution under cooling conditions,
followed by extraction with ethyl acetate. The extract was washed with
water and dried, after which the solvent was distilled off. The residue
was purified by silica gel colnmn chromatography (hexane:ethyl
acetate=2:1.fwdarw.1:1) to yield
6-chloro-1,2-dihydro-3-hydroxymethyl-1-methyl-2-oxo-4-phenylquinoline as
colorless crystals (1.90 g).
Melting point: 141.degree.-142.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.81 (3H, s), 3.96
(1H, b), 4.40 (2H, s), 7.17 (1H, d, J=2.4 Hz), 7.23-7.27 (2H, m), 7.38
(1H, d, J=9.2 Hz), 7.49-7.54 (4H, m)
Elemental analysis (for C.sub.17 H.sub.15 NO.sub.2 Cl):
Calculated (%): C, 67.89; H, 5.03; N, 4.66
Found (%): C, 67.63; H, 4.79; N, 4.55
Process 2:
While stirring a solution of 3-hydroxymethyl derivative obtained in Process
1 (1.80 g) in dichloromethane (45 ml) at 0.degree. C., triethylamine (1.08
ml) and methanesulfonyl chloride (0.61 ml) were added, followed by
stirring at for 1 hour. The reaction mixture was concentrated, and ethyl
acetate was added to the residue. This mixture was washed with water and
dried, after which the solvent was distilled off, to yield
6-chloro-1,2-dihydro-3-methanesulfonyloxymethyl-1-methyl-2-oxo-4-phenylqui
noline as colorless crystals (2.0 g) ›NMR (200 MHz, CDCl.sub.3) ppm: 3.14
(3H, s), 3.81 (3H, s), 5.00 (2H, s), 7.17-7.58 (8H, m)!.
Without purification, this compound was dissolved in DMSO (20 ml), and
sodium cyanide (2.0 g) was added, followed by stirring at room temperature
for 1 hour. To this reaction mixture was added ethyl acetate, and the
resulting mixture was washed with water and dried, after which the solvent
was distilled off, to yield
6-chloro-3-cyanomethyl-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline as
colorless crystals (1.43 g).
Melting point: 160.degree.-161.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.47 (2H, s), 3.84
(3H, s), 7.12 (1H, d, J=3.0 Hz), 7.21-7.31 (2H, m), 7.39 (1H, d, J=9.0
Hz), 7.53-7.61 (4H, m)
Elemental analysis (for C.sub.18 H.sub.13 N.sub.2 OCl):
Calculated (%): C, 70.02; H, 4.24; N, 9.07
Found (%): C, 69.75; H, 4.36; N, 8.81
Process 3:
A mixture of the compound obtained in Process 2 (1.10 g), acetic acid (10
ml) and hydrochloric acid (10 ml) was heated at 110.degree. C. for 2
hours. After the solvent was distilled off, ethyl acetate was added to the
residue. The mixture was washed with water and dried, after which the
solvent was distilled off, to yield the title compound as colorless
crystals (1.06 g).
Melting point: 195.degree.-199.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.50 (2H, s), 3.89
(3H, s), 7.18-7.59 (8H, m)
Elemental analysis (for C.sub.18 H.sub.14 NO.sub.3 Cl):
Calculated (%): C, 65.96; H, 4.31; N, 4.27
Found (%): C, 65.75; H, 4.34; N, 4.15
Reference Example 19
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineaceticacid
The isoquinoline-3-carboxylic acid obtained in Process 2 of Reference
Example 16 was reacted in substantially the same manner as in Process 1
and 2 of Reference Example 21 to yield the title compound as colorless
crystals.
Melting point: 217.degree.-220.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.22 (3H, s), 2.37
(3H, s), 3.63 (2H, s), 3.67 (3H, s), 5.90 (1H, brs), 6.75 (1H, s),
7.20-7.35 (2H, m), 7.40-7.55 (3H, m), 8.24 (1H, s)
Elemental analysis (for C.sub.20 H.sub.19 NO.sub.3):
Calculated (%): C, 74.75; H, 5.96; N, 4.36
Found (%): C, 74.69; H, 6.08; N, 4.23
Reference Example 20
6-Chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-acetic acid
Process 1:
6-Chloro-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid was reacted in
substantially the same manner as in Process 1 of Reference Example 18 to
yield 6-chloro-3-hydroxymethyl-1-oxo-4-phenyl-1H-2-benzopyran as colorless
crystals.
Melting point: 161.degree.-164.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.20 (1H, b), 4.30
(2H, s), 7.05 (1H, d, J=2.2 Hz), 7.28-7.53 (1H, d, J=2.0 Hz), 8.30 (1H, d,
J=8.6 Hz)
Elemental analysis (for C.sub.16 H.sub.11 O.sub.3 Cl):
Calculated (%): C, 67.03; H, 3.87
Found (%): C, 66.85; H, 3.95
Process 2:
The compound obtained in Process 1 was reacted with methanesulfonyl
chloride in the same manner as the reaction in Process 2 of Reference
Example 18 to yield
6-chloro-3-methanesulfonyloxymethyl-1-oxo-4-phenyl-1H-2-benzopyran as
colorless crystals.
Melting point: 179.degree.-180.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.10 (3H, s), 4.86
(2H, s), 7.08 (1H, d, J=2.0 Hz), 7.30-7.34 (2H, m), 7.53-7.58 (4H, m),
8.33 (1H, d, J=8.4 Hz)
Elemental analysis (for C.sub.17 H.sub.13 O.sub.5 ClS):
Calculated (%): C, 55.97; H, 3.59
Found (%): C, 55.69; H, 3.79
Process 3:
The compound obtained in Process 2 was reacted with sodium cyanide in the
same manner as the reaction in Process 2 of Reference Example 18 to yield
6-chloro-3-cyanomethyl-1-oxo-4-phenyl-1H-2-benzopyran as a pale yellow
oily substance.
NMR (200 MHz, CDCl.sub.3) ppm: 3.45 (2H, s), 7.01 (1H, d, J=2.2 Hz),
7.29-7.60 (6H, m),8.31(1H, d, J=8.6 Hz)
Process 4:
The compound obtained in Process 3 was reacted in the same manner as in
Process 3 of Reference Example 18 to yield the title. compound as
colorless crystals.
Melting point: 211.degree.-215.degree. C. (recrystallized from ethyl
acetate-ethyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.46 (2H, s), 6.99
(1H, d, J=2.0 Hz), 7.28-7.56 (6H, m), 8.28 (1H, d, J=8.4 Hz)
Elemental analysis (for C.sub.17 H.sub.11 O.sub.4 Cl.multidot.1/4H.sub.2
O):
Calculated (%): C, 63.96; H, 3.63
Found (%): C, 64.09; H, 3.64
Reference Example 21
6-Chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid
Process 1:
To a solution of 6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid
(6.1 g) in anhydrous THF (100 ml) were added oxalyl chloride (2.7 ml) and
DMF (several drops), followed by stirring at room temperature for 3 hours.
Upon solvent removal by distillation, an acid chloride was obtained as
colorless crystals. To a solution of this acid chloride in anhydrous THF
(100 ml) was added a solution of diazomethane in ethyl ether (prepared
from 12.0 g of N-nitrosomethyleurea), followed by stirring at room
temperature for 0.5 hours. Upon solvent removal by distillation, a
diazoketone derivative was obtained as an oily substance ›NMR (200 MHz,
CDCl.sub.3) ppm: 5.4 (1H, bs), 7.19 (1H, d, J=2.2 Hz), 7.3-7.4 (3H, m),
7.5-7.6 (4H, m); IRv.sub.max (Neat)cm.sup.-1 : 2100, 1720, 1620!.
This diazoketone derivative was dissolved in methanol (300 ml). While
stirring this solution with heating at 50.degree. C., silver oxide
(Ag.sub.2 O) (3.0 g) was added portionwise. After this mixture was stirred
for 3 hours with heating under reflux, it was filtered through Celite, and
the flitrate was distilled to remove the solvent. The residue was
fractionated and purified by silica gel column chromatography
(hexane:ethyl acetate=3:1) to yield
6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid ethyl ester as an
orange oily substance (4.14 g). This oily substance becomes colorless
crystals upon addition of ethyl acetate-hexane.
Melting point: 98.degree.-99.degree. C. (recrystallized from ethyl
acetate-hexane) NMR (200 MHz, CDCl.sub.3) ppm: 3.40 (2H, s), 3.68 (3H, s),
6.99 (1H, d, J=2.2 Hz), 7.2-7.6 (7H, m)
Elemental analysis (for C.sub.18 H.sub.13 O.sub.4 Cl):
Calculated (%): C, 65.76; H, 3.99
Found (%): C, 65.92; H, 3.84
Process 2:
A mixture of the crude compound obtained in Process 1 (4.1 g), acetic acid
(48 ml) and hydrochloric acid (24 ml) was heated under reflux for 1 hour.
After the solvent was distilled off, ethyl acetate was added to the
residue. This mixture was washed with water and dried, after which the
solvent was distilled off, followed by treatment of the residue with
isopropyl ether, to yield the title compound as pale yellow crystals (2.32
g).
Melting point: 174.degree.-177.degree. C. (recrystallized from isopropyl
ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.44 (2H, s), 7.01 (1H, d, J=2.4
Hz), 7.2-7.6 (7H, m)
Elemental analysis (for C.sub.17 H.sub.11 O.sub.4 Cl):
Calculated (%): C, 64.88; H, 3.52
Found (%): C, 65.13; H, 3.54
Reference Example 22
6-Methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid
Process 1:
A mixture of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid
ethyl ester ›prepared by heating 2-hydroxy-5-methylbenzophenone and
diethyl malonate in the presence of 1,8-diazabicyclo›5.4.0!undec-7-en;
melting point: 129.degree.-131.degree. C.; NMR (200 MHz, CDCl.sub.3) ppm:
0.96 (3H, t, J=7.2 Hz), 2.31 (3H, s), 4.07 (2H, q, J=7.2 Hz), 7.01 (1H,
bs), 7.2-7.4 (4H, m), 7.5-7.6 (3H, m)! (10.0 g), acetic acid (100 ml). and
hydrochloric acid (60 ml) was heated under reflux at 110.degree. C. for 15
hours. After the solvent was distilled off, ethyl acetate was added to the
residue. The mixture was washed with water and dried, after which the
solvent was distilled off, to yield
6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid as colorless
crystals (8.7 g).
Melting point: 260.degree.-262.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.31 (3H, s), 6.95
(1H, bs), 7.2-7.3 (2H, m), 7.39 (H, d, J=8.6 Hz), 7.5-7.6 (4H, m)
Elemental analysis (for C.sub.17 H.sub.12 O.sub.4):
Calculated (%): C, 72.85; H, 4.32
Found (%): C, 73.13;.H, 4.45
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 1 of Reference Example 21 to yield
6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-acetic acid methyl ester as
colorless crystals.
Melting point: 142.degree.-144.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.72 (3H, s), 3.39
(2H, s), 3.67 (3H, s), 6.79 (1H, brs), 7.2-7.3 (4H, m), 7.5-7.6 (3H, m)
Elemental analysis (for C.sub.19 H.sub.16 O.sub.4):
Calculated (%): C, 74.01; H, 5.23
Found (%): C, 73.75; H, 5.23
Process 3:
The compound obtained in Process 2 was reacted in substantially the same
manner as in Process 2 of Reference Example 21 to yield the title compound
as colorless crystals.
Melting point: 214.degree.-217.degree. C. (recrystallized from
chloroform-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.27 (3H, s),
3.42 (2H, s), 6.80 (1H, brs), 7.2-7.3 (4H, m), 7.5-7.6 (3H, m)
Elemental analysis (for C.sub.18 H.sub.14 O.sub.4):
Calculated (%): C, 73.46; H, 4.79
Found (%): C, 73.37; H, 4.79
Reference Example 23
6-Chloro-4-phenyl-3-quinolineacetic acid
Process 1:
While stirring a mixture of 6-chloro-4-phenyl-3-quinolinecarboxylic acid
methyl ester (8.0 g) and ethyl ether (100 ml) at 0.degree. C., lithium
aluminum hydride (1.0 g) was added, followed by stirring for 30 minutes.
After water (5 ml) was added, the mixture was stirred at room temperature
for 30 more minutes. After ethyl acetate was added; the insoluble material
was filtered off. The flitrate was washed by successively with aqueous
potassium carbonate and saturated aqueous sodium chloride and then dried,
after which the solvent was distilled off, to yield
6-chloro-3-hydroxymethyl-4-phenylquinoline as colorless crystals (6.05 g).
Melting point: 169.degree.-170.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 4.63 (2H, s),
7.20-7.35 (2H, m), 7.40-7.65 (5H, m), 8.07 (1H, d, J=8.8 Hz), 9.09 (1H, s)
Elemental analysis (for C.sub.16 H.sub.12 NOCl):
Calculated (%): C, 71.25; H, 4.48; N, 5.19
Found (%): C, 71.44; H, 4.51; N, 5.30
Process 2:
The compound obtained in Process 1 was reacted in substantially the same
manner as in Process 2 of Reference Example 18 to yield
6-chloro-3-cyanomethyl-4-phenylquinoline as colorless crystals.
Melting point: 149.degree.-151.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.65 (2H, s),
7.25-7.35 (2H, m), 7.43 (1H, d, J=2.2 Hz), 7.58-7.75 (4H, m), 8.12 (1H, d,
J=9.0 Hz), 9.04 (1H, s)
Elemental analysis (for C.sub.17 H.sub.11 N.sub.2 Cl):
Calculated (%): C, 73.25; H, 3.98; N, 10.05
Found (%): C, 72.86; H, 8.98; N, 10.86
Process 3:
The compound obtained in Process 2 was reacted in substantially the same
manner as in Process 3 of Reference Example 18 to yield the title compound
as colorless crystals.
Melting point: 211.degree.-213.degree. C. (recrystallized from
tetrahydrofuran-isopropyl ether)
NMR (200 MHz, CDCl.sub.3) ppm: 3.61 (2H, s), 4.10 (1H, bs), 7.25-7.85 (2H,
m), 7.43 (1H, d, J=2.2 Hz), 7.50-7.70 (4H, m), 8.19 (1H, d, J=8.8 Hz),
8.95 (1H, s)
Elemental analysis (for C.sub.17 H.sub.12 NO.sub.2 Cl.multidot.0.8H.sub.2
O):
Calculated (%): C, 65.41; H, 4.89; N, 4.49
Found (%): C, 65.42; l=I, 4.16; N, 4.66
Reference Example 24
4-(2-Methoxyphenyl)-1-oxo-1H-2-benzopyran-3-acetic acid
4-(2-Methoxyphenyl)-1-oxo-1H-2-benzopyran-3-carboxylic acid was reacted in
substantially the same manner as in Process 1 and 2 of Reference Example
21 to yield the title compound as colorless crystals.
Melting point: 148.degree.-144.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 3.44 (2H, s), 3.72
(3H, s), 6.9-7.6 (7H, m), 8.34 (1H, m)
Reference Example 25
6-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid
Process 1:
A mixture of 5-Chloro-2-hydroxy-2'-methylbenzophenone ›prepared by reaction
of 4-chloroanisole with ortho-toluoyl chloride in
1,1,2,2,-tetrachloroethane in the presence of aluminum chloride
(150.degree. C., 7 hours): melting point 65.degree.-66.degree. C.!(71.9g),
diethyl malonate (70 ml) and 1,8-diazabicyclo›5.4.0!undec-7-ene (4 ml) was
stirred at 170.degree. C. for 6 hours. The reaction mixture was purified
by silica gel column chromatography (hexane) to yield
6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid ethyl
ester as colorless crystals (73.2 g).
Melting point: 93.degree.-95.degree. C. (recrystallized from isopropyl
ether-hexane)
Process 2:
The compound obtained in Process 1 was reacted by a method similar to
Process 1 of Reference Example 22 to yield the title compound as colorless
crystals.
Melting point: 211.degree.-214.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.09 (3H, s),
6.9-7.1 (2H, m), 7.3-7.5 (4H, m), 7.64 (1H, dd, J=8.8, 2.2 Hz)
Reference Example 26
6-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid
The compound obtained in Reference Example 25 was reacted by a method
similar to Process 1 of Reference Example 21 to yield the methyl ester of
the title compound as an oil.
NMR (200 MHz, CDCl3) ppm: 2.09 (3H, s), 3.24 (1H, d, J=16.5 Hz), 3.43 (1H,
d, J=16.5 Hz), 3.66 (3H, s), 6.83 (1H, d, J=2.2 Hz), 7.10 (1H, m), 7.3-7.5
(5H, m)!
This compound was reacted by a method similar to Process 2 of Reference
Example 21 to yield the title compound as colorless crystals.
Melting point: 180.degree.-183.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.05 (3H, s), 3.27
(1H, d, J=16.8 Hz), 3.45 (1H, d, J=16.8 Hz), 6.83 (1H, d, J=2.2 Hz), 7.10
(1H, d, J=6.6 Hz), 7.3-7.5 (5H, m)
Reference Example 27
6-Chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid
Process 1:
A mixture of 5-chloro-2-hydroxy-2'-methoxybenzophenone ›prepared from
2-bromo-4-chloro-(2-methoxyethoxy)methoxybenzene and orthoanisaldehyde as
the starting materials: melting point, 94.degree.-98.degree. C.
(recrystallized from isopropyl ether)!(11.8 g), diethyl malonate (13.6 g)
and potassium fluoride (2.61 g) was heated at 180.degree. C. for 8.5
hours. After cooling, ethyl acetate was added to the mixture, washed with
water, dried and evaporated. The residue was subjected to silica gel
column chromatography (ethyl acetate:hexane: 1:10) to yield
6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid ethyl
ester as colorless crystals (7.78 g).
Melting point: 108.degree.-109.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
Process 2:
The compound obtained in Process 1 was subjected to hydrolysis by a method
similar to Process 2 of Reference Example 25 to yield
6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as
colorless crystals.
Melting point: 197.degree.-199.degree. C. (recrystallized from ethyl
acetate-methanol)
Process 3:
The compound obtained in Process 2 was subjected to carbon-elongation by a
method similar to Process 1 of Reference Example 26 to yield
6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid methyl
ester as colorless crystals.
Melting point: 182.degree.-183.degree. C. (recrystallized from ethyl
acetate)
Process 4:
The compound obtained in Process 3 was subjected to hydrolysis by a method
similar to Process 2 of Reference Example 26 to yield the title compound
as colorless crystals.
Melting point: 200.degree.-202.degree. C. (recrystallized from ethyl
acetate)
Reference Example 28
6-Chloro-2-oxo-4-›2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-acetic acid
Process 1:
5-Chloro-2-hydroxy-2'-(trifluoromethyl)benzophenone ›prepared from
2-bromo-4-chloro-(2-methyoxyethoxy)methoxybenzene and
ortho-(trifluoromethyl)benzaldehyde as the starting materials: melting
point, 71.degree.-72.degree. C. (recrystallized from hexane-isopropyl
ether)! was reacted by a method similar to Process 1 of Reference Example
25 to yield
6-chloro-2-oxo-4-›2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-carboxylic
acid ethyl ester as an oily substance.
NMR (200 MHz, CDCl.sub.3) ppm: 0.95 (3H, t, J=7.2Hz), 4.05 (2H, q, J=7.2
Hz), 6.81 (1H, d, J=2.4 Hz), 7.30-7.38 (2H, m), 7.54 (1H, dd, J=2.6, 8.8
Hz), 7.71 (2H, t, J=4.2 Hz), 7.82-7.90 (1H, m)
Process 2:
The compound obtained in Process 3 was reacted by a method similar to
Process 2 of Reference Example 25 to yield
6-chloro-2-oxo-4-›2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-carboxylic
acid as colorless crystals.
Melting point: 205.degree.-209.degree. C. (recrystallized from ethyl
acetate)
Process 3:
The compound obtained in Process 2 was subjected to carbon-elongation by a
method similar to Process 1 of Reference Example 26 to yield
6-chloro-2-oxo-4-›2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-acetic add
methyl ester as colorless crystals.
Melting point: 146.degree.-147.degree. C. (recrystallized from ethyl
acetate)
Process 4:
The compound obtained in Process 3 was reacted by a method similar to
Process 2 of Reference Example 26 to yield the title compound as colorless
crystals.
Melting point: 167.degree.-169.degree. C. (recrystallized from isopropyl
ether)
Reference Example 29
2,6,7-Trimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
Process 1:
A mixture of 2-benzoyl-4,5-dimethylbenzoic acid (11.4 g), acetone (300 ml),
DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate (12.84
g) was stirred at room temperature for 60 hours. After the solvent was
distilled off, ethyl acetate was added to the residue. This mixture was
washed with water and then dried, after which the solvent was distilled
off. To the residue were added acetic acid (180 ml) and hydrochloric acid
(180 ml), followed by heating at 110.degree. C. for 5 hours. The reaction
mixture was concentrated, and water was adored to the concentrate,
followed by extraction with ethyl acetate. The extract was washed with
water and then dried, after which the solvent was distilled off, to yield
colorless crystals. The crystals were recrystallized from ethyl
acetate-isopropyl ether to yield
6,7-dimethyl-4-phenylisocoumarin-3-carboxylic acid
(.ident.6,7-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid).
Melting point: 265.degree.-268.degree. C.
Process 2:
To a solution of the compound (3.75 g) obtained in Process i in methanol
(50 ml) was added a 40% methylamine-methanol solution (25 ml), followed by
stirring at room temperature for 2 hours. After the solvent was distilled
off, 4N-HCl-ethyl acetate (50 ml) was added to the residue, followed by
stirring at room temperature for 2 hours. After the solvent was distilled
off, water was added to the residue, and the precipitated crystals were
collected by filtration and then washed with water, acetone and ethyl
ether to yield the title compound as colorless crystals (3.51 g).
Melting point: >300.degree. C. (recrystallized from ethanol) NMR (200 MHz,
CDCl.sub.3 +DMSO-d.sub.6) ppm: 2.25 (3H, s), 2.39 (3H, s), 3.67 (3H, s),
6.91 (1H, s), 7.39-7.42 (5H, m), 8.24 (1H, s)
Elemental analysis (for C.sub.19 H.sub.17 NO.sub.3):
Calculated: C, 74.25; H, 5.58; N, 4.56
Found: C, 74.40; H, 5.50; N, 4.41
The compound obtained in Process 1 of Reference Example 29 was reacted with
ethylamine, n-butylamine, N,N-dimethylaminoethylenediamine or ammonia, in
place of methylamine, in the same manner as in Process 2, to yield the
compounds of Reference Examples 30 through 33 as colorless crystals.
Reference Example 30
2-Ethyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
Melting point: 254.degree.-256.degree. C. (recrystallized from ethyl
acetate-methanol)
Reference Example 31
2-n-Butyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
Melting point: 218.degree.-219.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Reference Example 32
2-(2-Dimethylaminoethyl)-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carbo
xylic acid
Melting point: 291.degree.-293.degree. C. (recrystallized from
chloroform-methanol)
Reference Example 33
6,7-Dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
Melting point: 325.degree.-327.degree. C. (recrystallized from
chloroform-methanol)
Reference Example 34
4-(4-Fluorophenyl)-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylic acid
4,5-Dimethyl-2-(4-fluorobenzoyl)benzoic acid, in place of
2-benzoyl-4,5-dimethylbenzoic acid, was reacted and treated in the same
manner as in Process 1 of Reference Example 29 to yield
4-(2-fluorophenyl)-6,7-dimethylisocoumarin-3-carboxylic acid ›melting
point 214.degree.-217.degree. C. (recrystallized from ethyl acetate)!.
This compound was reacted in the same manner as in Process 2 of Reference
Example 29 to yield the title compound as colorless crystals.
Melting point: 309.degree.-312.degree. C. (recrystallized from
chloroform-methanol)
Reference Example 35
5-Fluoro-4-(4-fluorophenyl)-2-methyl-1(2H)-isoquinolinone-3-carboxylic acid
5-Fluoro-4-(4-fluorophenyl)isocoumarin-3-carboxylic acid and methylamine
were reacted in the same manner as in Process 2 of Reference Example 29 to
yield the title compound as colorless crystals.
Melting point: 256.degree.-257.degree. C. (recrystallized from
acetone-isopropyl ether)
Reference Example 36
6,7-Dichloro-2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
2-Benzoyl-4,5-dichlorobenzoic acid, in place of
2-benzoyl-4,5-dimethyl-benzoic acid, was reacted and treated in the same
manner as in Process 1 of Reference Example 29 to yield
6,7-dichloro-4-phenylisocoumarin-3-carboxylic acid ›melting point
243.degree.-244.degree. C. (recrystallized from ethyl acetate-isopropyl
ether)!. This compound was reacted and treated in the same manner as in
Process 2 of Reference Example 29 to yield the title compound as colorless
crystals.
Melting point: >300.degree. C. (recrystallized from chloroform-methanol)
Reference Example 37
2-›2-(N,N-Dimethylamino)ethyl!-4-phenyl-1-(2H)-isoquinolinone-3-carboxylic
acid
1-Oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid and
N,N-dimethylaminoethylenediamine were reacted by a method similar to
Process 1 and 2 of Reference Example 29 to yield the title compound as
colorless crystals.
Melting point: 295.degree.-296.degree. C. (recrystallized from chloroform
methanol-dichloromethane-ethyl ether)
Reference Example 38
2,6,7-Trimethyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylic acid
Process 1:
A mixture of 4,5-dimethyl-2-(2-methylbenzoyl)benzoic acid (7.7 g),
dichloromethane (100 ml), oxalyl chloride (2.74 ml) and DMF (3 drops) was
stirred at room temperature for 2 hours. After the solvent was distilled
off, dichloromethane (50 ml) was added to the residue. This mixture was
added dropwise to a mixture of N-methylaminoacetonitrile hydrochloride
(4.86 g), triethylamine (12.0 ml) and dichloromethane (70 ml), while
stirring with ice cooling. This mixture was stirred at room temperature
for 12 hours. After the solvent was distilled off, ethyl acetate was added
to the residue. The mixture was washed successively with water, dilute
hydrochloric acid, sodium hydrogen carbonate and water and then dried,
after which the solvent was distilled off, to yield
4,5-dimethyl-2-(2-methylbenzoyl)benzoic acid-N-cyanomethyl-N-methylamide
as a colorless oily substance (9.2 g). NMR (200 MHz, CDCl.sub.3) ppm: 2.26
(3H, s), 2.35 (3H, s), 2.37 (3H, s), 2.99 (3H, s), 4.47 (2H, s), 7.05-7.40
(6H, m)
Process 2:
A mixture of the compound (9.1 g) obtained in Process 1, toluene (200 ml)
and 1,8-diazabicyclo›5.4.0!undec-7-ene (8 ml) was stirred for 7 hours
under refluxing. After ethyl acetate was added, the reaction mixture was
washed successively with water, dilute hydrochloric acid, aqueous sodium
hydrogen carbonate and water and then dried, after which the solvent was
distilled off, to yield
3-cyano-2,6,7-trimethyl-4-(2-methylphenyl)-1(2H)-isoquinolinone as
colorless crystals (6.3 g).
Melting point: 217.degree.-218.degree. C. (recrystallized from ethyl
acetate)
Process 3:
The compound (5.8 g) obtained in Process 2, ethanol (20 ml) and 1N sodium
hydroxide (25 ml) were stirred for 3 hours under refluxing. The reaction
mixture was concentrated, dilute hydrochloric acid was added to the
concentrate, and the precipitated crystals were collected by filtration.
The crystals were washed with water, acetone and ethyl ether to yield
2,6,7-trimethyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylic acid
amide as colorless crystals (6.1 g).
Melting point: 296.degree.-299.degree. C. (recrystallized from methanol)
Process 4:
To a mixture of the compound (1.0 g) obtained in Process 3, acetic acid (15
ml) and concentrate hydrochloric acid (30 ml) was added portionwise sodium
nitrite (6.2 g) at room temperature, followed by stirring for 5 hours. To
the reaction mixture was added water, and the precipitated crystals were
collected by filtration, which were then washed with water, acetone and
ethyl ether, to yield the title compound as colorless crystaIs (0.97 g).
Melting point: 291.degree.-292.5.degree. C. (recrystallized from ethyl
acetate)
2-Benzoylbenzoic acids having respective corresponding substituents, in
place of 4,5-dimethyl-2-(2-methylbenzoyl)benzoic acid of Process 1 of
Reference Example 38, were reacted and treated in the same manner as in
processes 2 through 4 to yield the compounds of Reference Example 39 to 45
as colorless crystals.
Reference Example 39
4-(2,6-Dimethylphenyl)-2-methyl-1(2H)-isoquinolinone-3-carboxylic acid
Melting point: 284.degree.-285.5.degree. C. (recrystallized from
methanol-ethanol)
Reference Example 40
4-(4-Fluoro-2-methylphenyl)-2-methyl-1(2H)-isoquinolinone-3-carboxylic acid
Melting point: 257.5.degree.-260.degree. C. (recrystallized from ethyl
acetate-ethanol)
Reference Example 41
2-Methyl-4-(2-methylphenyl)-1(2H)-isoquinolinone-3-carboxylic acid
Melting point: 225.degree.-227.degree. C. (recrystallized from ethyl
acetate-ethanol)
Reference Example 42
4-(2-Ethylphenyl)-2-methyl-1(2H-isoquinolinone-3-carboxylic acid
Melting point: 100.degree.-102.degree. C. ›2/3 hydrate!(recrystallized from
ethyl acetate-isopropyl ether)
Reference Example 43
4-(2-Ethylphenyl)-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylic acid
Melting point: 214.degree.-215.degree. C. (recrystallized from ethyl
acetate-ethanol)
Reference Example 44
4-(2,6-Dimethylphenyl)-2,6,7-trimethyl-1(2H)-isoquinolinone-3-carboxylic
acid
Melting point: >300.degree. C. (recrystallized from ethyl acetate-ethanol)
Reference Example 45
2-Methyl-4-›2-(trifluoromethyl)phenyl!-1-(2H)-isoquinolinone-3-carboxylic
acid
Melting point: 250.degree.-253.degree. C. (recrystallized from ethyl
acetate-THF)
Reference Example 46
5,6,7,8-Tetrahydro-2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
Process 1:
To a solution of 2-benzoyl-1-cyclohexenecarboxylic acid ›prepared from
3,4,5,6-tetrahydrophtalic anhydride by reacting with aluminum chloiride in
benzene! (7.05 g) in THF (100 ml) were added DMF (a few drops) and oxalyl
chloride (3.20 ml) at room temperature, and the mixture was stirred for 2
hours. The solvent was evaporated, and the residue was dissolved in THF
(50 ml). The solution was added dropwise to a stirred mixture of
N-methylglycine ethyl ester hydrochloride (5.64 g), THF (100 ml) and
triethylamine (12.0 ml) at 0.degree. C. The mixture was stirred at room
temperature for 2 hours and under reflux for 4 hours, and the solvent was
evaporated. To the residue was added ethyl acetate. The mixture was washed
successively with water, diluted hydrochloric acid, water, aqueous sodium
hydrogen carbonate and water, dried, and the solvent was evaporated to
yield N-(2-benzoyl-1-cyclohexenecarbonyl)-N-methylglycine ethyl ester as a
paIe yellow oil (9.73 g). To the solution of this compound in THF (250 ml)
was added pottasinm t-butoxide (3.97 g) at 0.degree. C. with stirring, and
the mixture was stirred for 10 minutes at room temperature. The solvent
was evaporated, and to the residue was added ethyl acetate. The mixture
was washed with water, dried and the solvent was evaporated to yield
5,6,7,8-tetrahydro-2-methyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic
acid ethyl ester as colorless crystals (1.86 g).
Melting point: 131.degree.-132.degree. C. (recrystallized from isopropyl
ether)
Process 2:
A mixture of the compound obtained in Process 1 (1.00 g), dioxane (20 ml),
and 1N-NaOH (20 ml) was refluxed for 2 hours. The solvent was evaporated,
and to the residue was added water. The mixture was acidified with
hydrochloric acid, and extracted with ethyl acetate. The extract was
washed with water, dried, and the solvent was evaporated to yield the
title compound as colorless crystals (519 mg).
Melting point: 226.degree.-227.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Reference Example 47
1,2-Dihydro-3-hydroxymethyl-2,6,7-trimethyl- 1-oxo-4-phenylisoquinoline
To a solution of the compound (9.27 g) obtained in Reference Example 29 in
THF (100 ml) were added oxalyl chloride (3.7 ml) and DMF (10 drops) at
room temperature, followed by stirring for 30 minutes. After the solvent
was distilled off, the residue was dissolved in THF (50 ml). This solution
was gradually added at 0.degree. C. to a suspension of sodium borohydride
(5.0 g) in dimethoxyethane (100 ml). After stirring at 0.degree. C. for 30
minutes, the reaction mixture was added to 2N hydrochloric acid at
0.degree. C., followed by extraction with ethyl acetate. The extract was
washed with aqueous sodium hydrogen carbonate and water and then dried,
after which the solvent was distilled off, to yield the title compound as
a colorless crystals (7.18 g).
Melting point: 209.degree.-210.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.09 (1H, bt,
J=5.8 Hz), 2.20 (3H, s), 2.34 (3H, s), 3.81 (3H, s), 4.43 (2H, d, J=5.8
Hz), 6.73 (1H, s), 7.25-7.35 (2H, m), 7.45-7.55 (3H, m), 8.19 (1H, s)
1(2H)-Isoquinolinone-3-carboxylic acids having respective corresponding
substituents were reduced in the same manner as in Reference Example 47 to
yield the compounds of Reference Examples 48 to 51 as colorless crystals.
Reference Example 48
1,2-Dihydro-3-hydroxymethyl-2-methyl-1-oxo-4- phenylisoquinoline
Melting point: 158.degree.-159.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Reference Example 49
1,2-Dihydro-3-hydroxymethyl-2-methyl-4-(2-methylphenyl)-1-oxoisoquinoline
Melting point: 167.degree.-168.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Reference Example 50
6-Chloro-1,2-dihydro-3-hydroxymethyl-2-methyl-1-oxo-4-phenyisoquinoline
Melting point: 193.degree.-195.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
Reference Example 51
2-Ethoxycarbonylmethyl-1,2-dihydro-3-hydroxymethyl-6,7-dimethyl-1-oxo-4-phe
nylisoquinoline
Melting point: 176.degree.-178.degree. C. (recrystallized from ethyl
acetate)
Reference Example 52
1,2-Dihydro-3-methanesulfonyloxymethyl-2,6,7-trimethyl-1-oxo-4-phenylisoqui
noline
To a solution of the compound (3.0 g) obtained in Reference Example 47 in
dichloromethane (100 ml) were added triethylamine. (3.8 ml) and
methanesulfonyl chloride (1.3 ml), while stirring the solution at
0.degree. C., followed by stirring for 30 minutes. After dichloromethane
was added, the reaction mixture was washed with a 5% aqueous phosphoric
acid solution and water and then dried, after which the solvent was
distilled off, to yield the title compound as colorless crystals (2.98 g).
Melting point: 150.degree.-151.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 2.25 (3H, s), 2.40
(3H, s), 2.86 (3H, s), 3.77 (3H, s), 5.01 (2H, s), 6.82 (1H, s), 7.25-7.35
(2H, m), 7.45-7.60 (3H, m), 8.27 (1H, s)
Elemental analysis (for C.sub.20 H.sub.21 NO.sub.4 S):
Calculated: C, 64.67; H, 5.70; N, 3.77
Found: C, 64.59; H, 5.69; N, 3.67
3-Hydroxylmethylisoquinol:ines having respective corresponding substituents
were reacted with methanesulfonyl chloride in the some manner as in
Reference Example 52 to yield the compounds of Reference Example 53 to 55
as colofiess crystals.
Reference Example 53
1,2-Dihydro-3-methanesulfonyloxymethyl-2-methyl-1-oxo-4-phenylisoquinoline
Melting point: 149.degree.-150.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Reference Example 54
1,2-Dihydro-3-methanesulfonyloxymethyl-2-methyl-4-(2-methylphenyl)-1-oxoiso
quinoline
Melting point: 149.degree.-150.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Reference Example 55
6-Chloro-1,2-dihydro-3-methanesulfonyloxymethyl-2-methyl-1-oxo-4-phenylisoq
uinoline
Melting point: 168.degree.-165.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Reference Example 56
1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3- isoquinolineacetic acid
Process 1:
The compound (6.4 g) obtained in Reference Example 52 was dissolved in DMSO
(80 ml), and sodium cyanide (5.0 g) was added, followed by stirring at
room temperature for 30 minutes. After ethyl acetate was added, this
reaction mixture was washed with water and then dried, after which the
solvent was distilled off, to yield
3-cyanomethyl-1,2-dihydro-2,6,7-trimethyl-1-oxo-4- phenylisoquinoline as
colorless crystals (4.7 g).
Melting point: 186.degree.-188.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Process 2:
A mixture of the compound (4.7 g) obtained in Process 1, acetic acid (150
ml) and hydrochloric acid (150 ml) was heated at 110.degree. C. for 7
hours. After the solvent was distilled off, ethyl acetate was added to the
residue. The mixture was washed with water and then dried, after which the
solvent was distilled off, to yield the title compounds colorless crystals
(3.7 g).
The physico-chemical data of this compound were identical with those of the
compound obtained in Reference Example 19.
Reference Example 57
The compound obtained in Reference Example 55 was reacted by a method
similar to Process 1 and 2 of Reference Example 56 to yield the following
compounds.
Process 1:
6-Chloro-3-cyanomethyl-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinoline
Melting point: 229.degree.-231.degree. C. (recrystallized from ethyl
acetate)
Process 2:
6-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetic acid
Melting point: 216.degree.-217.degree. C. (recrystallized from ethyl
acetate-acetone)
Reference Example 58
1,2-Dihydro-3-(2-hydroxyethyl)-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline
To a solution of the compound (700 mg) obtained in Reference Example 56 in
THF (10 ml) were added oxalyl chloride (0.3 ml) and DMF (one drop) at room
temperature, followed by stirring for 30 minutes. After the solvent was
distilled off, the residue was dissolved in THF (5 ml). This solution was
gradually added at 0.degree. C. to a suspension of sodium borohydride (0.5
g) in dimethoxyethane (10 ml). After stirring at 0.degree. C. for 20
minutes, the reaction mixture was added to 2N hydrochloric acid at
0.degree. C., followed by extraction with ethyl acetate. The extract was
washed with aqueous sodium hydrogen carbonate and water and then dried,
after which the solvent was distilled off, to yield the title compound as
colorless crystals (571 mg).
Melting point: 204.degree.-207.degree. C. (recrystallized from ethyl
acetate-isopropyl ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.90 (1H, bs),
2.19 (3H, s), 2.34 (3H, s), 2.84 (2H, t, J=7.1 Hz), 3.60-3.80 (2H, m),
3.73 (3H, s), 6.62 (1H, s) 7.20-7.30 (2H, m), 7.35-7.50 (3H, m), 8.16 (1H,
s)
Reference Example 59
2-Ethoxycarbonylmethyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxy
lic acid
Process 1:
To a solution of the compound (1.172 g) of Reference Example 33 in acetone
(20 ml)-DMF (5 ml) were added benzyl bromide (0.586 ml) and potassium
carbonate (608 mg), followed by heating under reflux for 2.5 hours. After
the solvent was distilled off, ethyl acetate was added to the residue,
which was then washed with water and then dried, followed by solvent
removal by distillation, to yield
6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid benzyl ester
as colorless crystals (700 mg).
Melting point: 166.degree.-169.degree. C. (recrystallized from ethyl
acetate)
Process 2:
To a solution of the compound (700 mg) obtained in Process 1 in DMF (5 ml)
was added sodium hydride (60% in oil) (80 mg), followed by stirring at
room temperature for 15 minutes. To this mixture was added ethyl
bromoacetate (0.222 ml) with ice cooling, followed by stirring at room
temperature for 30 minutes. The reaction mixture was poured into water and
extracted with ethyl acetate, after which the extract was washed with
water and then dried. After the solvent was distilled off, the residue was
subjected to silica gel column chromatography (hexane:ethyl acetate=9:1)
to yield
2-ethoxycarbonylmethyl-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-carbox
ylic acid benzyl ester as colorless crystals (450 mg).
Melting point: 139.5.degree.-140.5.degree. C. (recrystallized from ethyl
acetate-hexane)
Process 3:
To a solution of the compound (400 mg) obtained in Process 2 in ethanol (15
ml) was added 10% palladium carbon (100 mg), followed by stirring at room
temperature in a hydrogen atmosphere for 1.5 hours. The catalyst was
filtered off, and the filtrate was distilled to remove the solvent. The
residue was subjected to silica gel column chromatography
(chloroform:methanol=4:1) to yield the title compound as colorless
crystals (280 mg).
Melting point: 210.degree.-213.degree. C. (recrystallized from methanol)
Reference Example 60
2-(3-Ethoxycarbonylpropyl)-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
A mixture of 4-phenylisocoumarin-3-carboxylic acid (1.30 g),
4-amino-n-butyric acid ethyl ester (2.75 g) and ethanol (8 ml) was heated
under reflux for 14 hours while stirring. After the solvent was distilled
off, ethyl acetate was added to the residue. This mixture was washed with
dilute hydrochloric acid and water and then dried, after which the solvent
was distilled off. To the residue were added ethyl acetate (10 ml) and 4N
HCl-ethyl acetate (20 ml), followed by stirring at room temperature for 3
hours. After ethyl acetate was added, the reaction mixture was washed with
water and then dried, followed by solvent removal by distillation, to
yield the title compound as colorless crystals (1.83 g).
Melting point: 154.degree.-156.degree. C. (recrystallized from ethyl
acetate-ethyl ether)
Reference Example 61
1-Amino-1,2,3,4-tetrahydro-6-oxo-11-phenyl-6H- benzo›b!quinolizine
Process 1:
The compound (393 mg) obtained in Reference Example 60 was dissolved in DMF
(2 ml). While stirring this solution with ice cooling, sodium hydride (60%
in oil) (50 mg) was added, followed by stirring for 15 minutes. To this
mixture was added ethyl iodide (0.15 ml), followed by stirring at room
temperature for 2 hours, after which the solvent was distilled off. To the
residue was added ethyl acetate, and the mixture was washed with water and
then dried, after which the solvent was distilled off, to yield
2-(3-ethoxycarbonylpropyl)-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid
ethyl ester as colorless crystals (390 mg).
Melting point: 98.degree.-99.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
Process 2:
The compound (6.75 g) obtained in Process 1 was dissolved in dry THF (150
ml). While stirring this solution at room temperature, sodium hydride (60%
in oil) (1.50 g) was added. This mixture was heated under reflux for 1
hour. After the reaction mixture was concentrated, ethyl acetate was added
to the concentrate, which was then washed successively with dilute
hydrochloric acid, water and aqueous sodium hydrogen carbonate and then
dried, after which the solvent was distilled off, to yield
2-ethoxycarbonyl-1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6H-benzo›b!quinoli
zine as pale yellow crystals (5.25 g).
Melting point: 167.degree.-169.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 1.33 (3H, t, J=7 Hz), 2.67 (2H, t,
J=6 Hz), 4.27 (4H, m), 7.06-7.55 (8H, m), 8.51 (1H, m), 12.04 (1H, s) ›
This product has an enol structure.!
Process 3:
A mixture of the compound (2.0 g) obtained in Process 2, acetic acid (15
ml), concentrate hydrochloric acid (4 ml), ethanol (3 ml) and water (3 ml)
was heated under reflux for 5 hours while stirring, followed by solvent
removal by distillation. To the residue was added water, and the
precipitated crystals were collected by filtration and then washed with
water, ethanol and ether, to yield
1,2,3,4-tetrahydro-1,6-dioxo-11-phenyl-6H-benzo›b!quinolizine as yellow
crystals (1.48 g).
Melting point: 223.degree.-225.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 2.27 (2H, m), 2.67 (2H, t, J=6.5
Hz), 4.37 (2H, m), 7.15-7.62 (8H, m), 8.55 (1H, m)
Elemental analysis (for C.sub.19 H.sub.15 NO.sub.2):
Calculated: C, 78.87; H, 5.23; N, 4.84
Found: C, 78.65; H, 5.36; N, 4.88
Process 4:
A mixture of the compound (1.16 g) obtained in Process 3, hydroxylamine
hydrochloride (2.78 g), sodium acetate (3.28 g) and ethanol (50 ml) was
heated under reflux for 4 hours, followed by solvent removal by
distillation. To the residue was added water, and the precipitated
colorless crystals were collected by filtration and then washed with
water, ethanol and ether, to yield an oxime derivative as colorless
crystals (1.18 g) .
Melting point: 277.degree.-279.degree. C. (decomposed) (recrystallized from
chloroform-methanol) NMR (200 MHz, CDCl.sub.3) ppm: 2.04 (2H, m), 2.80
(2H, t, J=7.4 Hz), 2.23 (2H, m), 7.20-7.55 (8H, m), 8.52 (1H, m)
Process 5:
To a suspension of the compound (500 mg) obtained in Process 4 in ethanol
(20 ml) were added ammonium acetate (138 mg), zinc powder (520 mg) and 40%
aqueous ammonia (10 ml), followed by heating under reflux for 5 hours. The
precipitate was filtered off, and the filtrate was distilled to remove the
solvent. After ethyl acetate was added, the residue was washed with water.
The ethyl acetate layer was extracted with 2N HCl. The extract was
alkalinized by addition of potassium carbonate and then extracted with
ethyl acetate, washed with water and then dried, after which the solvent
was distilled off, to yield the title compound as colorless crystals (205
mg).
Melting point: 183.degree.-185.degree. C. (recrystallized from ethyl
acetate-ether) NMR (200 MHz, CDCl.sub.3) ppm: 1.7-2.3 (4H, m), 4.13 (1H,
t, J=3 Hz), 4.32 (2H, t, J=7 Hz), 6.96 (1H, m), 7.26-7.55 (7H, m), 8.49
(1H, m)
Reference Example 62
1,2,3,4-Tetrahydro-1-hydroxy-6-oxo-11-phenyl-6H-benzo›b!quinolizine
To a suspension of the compound (250 mg) obtained in process 3 of Reference
Example 61 in methanol (15 ml) was added sodium borohydride (40 mg) at
room temperature, followed by stirring for 1 hour. The reaction mixture
was concentrated, and dilute hydrochloric acid was added to the
concentrate, followed by extraction with ethyl acetate. The extract was
washed with water and then dried, after which the solvent was distilled
off, to yield the title compound as pale yellow crystals (235 mg).
Melting point: 220.degree.-222.degree. C. (recrystallized from ethyl
acetate) NMR (200 MHz, CDCl.sub.3) ppm: 1.70-2.30 (4H, m), 4.10-4.45 (2H,
m), 4.75 (1H, t, J=3.2 Hz), 6.99-7.03 (1H, m), 7.25-7.53 (7H, m), 8.49
(1H, m)
Reference Example 63
2-(3-Ethoxycarbonylpropyl)-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-car
boxylic acid
The compound obtained in Process 1 of Reference Example 29 and
4-amino-n-butyric acid ethyl ester were reacted and treated in the same
manner as in Reference Example 60 to yield the title compound as a
colorless oily substance.
NMR (200 MHz, CDCl.sub.3) ppm: 1.13 (3H, t, J=7.2 Hz), 2.16 (2H, m), 2.26
(3H, s), 2.39 (3H, s), 2.42 (2H, m), 3.97 (2H, q, J=7.2 Hz), 4.16 (2H, m),
6.92 (1H, s), 7.32-7.48 (3H, m), 8.23 (1H, s)
Reference Example 64
1-Amino-1,2,3,4-tetrahydro-6-oxo-11-phenyl-6H-benzo›b!quinolizine
The compound obtained in Reference Example 63 was reacted and treated in
the same manner as in Process 1 through 5 of Reference Example 61 to yield
the title compound. The intermediate compounds obtained in the respective
process and their physico-chemical constants are given below.
Process 1:
2-(3-Ethoxycarbonylpropyl)-6,7-dimethyl-4-phenyl-1(2H)-isoquinolinone-3-car
boxylic acid ethyl ester
A colorless oily substance
NMR (200 MHz, CDCl.sub.3) ppm: 0.90 (3H, t, J=7.2 Hz), 1.25 (3H, t, J=7.2
Hz), 2.12 (2H, m), 2.26 (3H, s), 2.39 (2H, m), 2.40 (3H, s), 3.95-4.20
(6H, m), 6.95 (1H, s), 7.24-7.50 (5H, m), 8.25 (1H, s)
Process 2:
2-Ethoxycarbonyl-1,2,3,4-tetrahydro-8,9-dimethyl-1,6-dioxo-11-phenyl-6H-ben
zo›b!quinolizine
Melting point: 166.degree.-168.degree. C. (recrystallized from ethyl
acetate)
Process 3:
1,2,3,4-Tetrahydro-8,9-dimethyl-1,6-dioxo-11-phenyl-6H-benzo›b!quinolizine
Melting point: 203.degree.-206.degree. C. (recrystallized from ethyl
acetate)
Process 4:
1,2,3,4-Tetrahydro-1-hydroxyimino-8,9-dimethyl-1,6-dioxo-11-phenyl-6H-benzo
›b!quinolizine
Melting point: 247.degree.-250.degree. C. (decomposed) (recrystallized from
ethanol)
Process 5:
Title compound (recrystallized from ethyl acetate)
Melting point: 175.degree.-177.degree. C. (recrystallized from ethyl
acetate)
Reference Example 65
1,2,3,4-Tetrahydro-1-hydroxy-8,9-dimethyl-6-oxo-11-phenyl-6H-benzo›b!quinol
izine
The compound obtained in Process 3 of Reference Example 64 was reacted
(reduced) and treated in the same manner as in Reference Example 62 to
yield the title compound as colorless crystals.
Melting point: 210.degree.-212.degree. C. (recrystallized from ethyl
acetate)
Reference Example 66
1,2,3,4-Tetrahydro-1,6-dioxo-11-phenyl-6H-pyrazino›1,2-b!isoquinoline
A mixture of 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid (500 mg) and
ethylenediamine (15 ml) was stirred at room temperature overnight. After
evaporation of the solvent, concentrated hydrochloric acid (10 ml) and
acetic acid (10 ml) were added to the residue. The mixture was heated
under reflux for 48 hours. To the mixture was added water, and extracted
with ethyl acetate. The extract was washed successively with water,
aqueous sodium hydrogen carbonate and water, dried, and evaporated to
yield the title compound as colorless crystals (115 mg).
Melting point: >300.degree. C. (recrystallized from ethyl acetate)
Reference Example 67
1,2,3,4-Tetrahydro-6-oxo-11 -phenyl-6H-pyrazino›1,2-b!isoquinoline
Process 1:
1-Oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid (3.0 g) was subjected to
reduction by a method similar to Reference Example 47 to yield
3-hydroxymethyl-1-oxo-4-phenyl-1H-2-benzopyran as colorless crystals (2.6
g).
Melting point: 109.degree.-110.degree. C. (recrystallized from ethyl
acetate-hexane)
Process 2:
The compound obtained in Process 1 (2.5 g) was oxidized with SO.sub.3
-pyridine complex in DMSO in the presence of triethylarnine to yield
1-oxo-4-phenyl-1H-2-benzopyran-3-carboxaldehyde as colorless crystals
(2.38 g).
Melting point: 179.degree.-181.degree. C. (recrystallized from ethyl
acetate-THF)
Process 3:
A mixture of the compound obtained in Process 2 (500 mg) and
ethylenedismine (15 ml) was stirred at room temperature for 5 hours. After
evaporation of the solvent, water was added to the residue, and the
mixture was extracted with ethyl acetate. The extract was washed with
water, dried, and evaporated. To the residue was added concentrated
hydrochloric acid (5 ml) and the mixture was stirred at room temperature
overnight. After neutaralization, the mixture was extracted with ethyl
acetate. The extract was washed with water, dried, and evaporated to yield
3,4-dihydro-6-oxo-11-phenyl-6H-pyrazino›1,2-b!isoquinoline as color
crystals (280 mg).
Melting point: 181.degree.-183.degree. C. (recrystallized from ethyl
acetate)
Process 4:
To a mixture of the compound obtained in Process 3 (260 mg), acetic acid
(60 .mu.l) and methnol (10 ml) was added sodium cyanoborohydride (120 mg),
and the mixture was stirred for 30 minutes at room temperature. After
evaporation of the solvent, aqueous sodium hydrogen carbonate was added to
the residue, and the mixture was extracted with ethyl acetate. The extract
was washed with water, dried, and evaporated to yield the title compound
as colorless crystals (240 mg).
Melting point: 154.degree.-156.degree. C. (recrystallized from ethyl
acetate)
Reference Example 68
1,2-Dihydro-3-mercaptomethyl-2-methyl-4-(2-methylphenyl)-1-oxoisoquinoline
A mixture of the compound obtained in Reference Example 54 (1.8 g), sodium
hydrosulfide-methanol solution (2.73M) (3 ml), THF (25 ml), and methanol
(10 ml) was stirred for 1 hour at room temperature. After evaporation of
the solvent, dilute hydrochloric acid was added to the residue, and the
mixture was extracted with ethyl acetate. The extract was washed with
dilute hydrochloric acid and water, dried, and evaporated. The residue was
subjected to silica gel column chromatography (ethyl acetate:hexane=3:1)
to yield the title compound as colorless crystals (503 mg).
Melting point: 184.degree.-186.degree. C. (recrystallized from ethyl
acetate-isopropyl ether)
FORMULATION EXAMPLE
Tablets
Of the components given below, to the compound of Example 101, corn starch
and lactose were added with aqueous hydroxypropylcellulose, and the
mixture was kneaded, then dried and crushed to give granules.
To this was added magnesium stearate and, after admixing, the whole mixture
was made up into tablets each weighing 200 mg on a rotary tableting
machine.
Composition per tablet:
______________________________________
Compound of Example 101 50 mg
Lactose 100 mg
Corn starch 43.4 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
Total 200 mg
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